Furan and thiophene derivatives that activate human peroxisome profilerator activated receptors

ABSTRACT

A compound of formula (I) or pharmaceutically acceptable salts and solvates thereof, for the treatment of a hPPAR mediated disease or condition.

[0001] The present invention relates to certain novel compounds. Inparticular, the present invention relates to compounds that activatehuman peroxisome proliferator activated receptors (“hPPARs”). Thepresent invention also relates to method for preparing the compounds,their use in medicine, pharmaceutical compositions containing them andmethods for the prevention or treatment of PPAR mediated diseases orconditions.

[0002] Several independent risk factors have been associated withcardiovascular disease. These include hypertension, increased fibrinogenlevels, high levels of triglycerides, elevated LDL cholesterol, elevatedtotal cholesterol, and low levels of HDL cholesterol. HMG CoA reductaseinhibitors (“statins”) are useful for treating conditions characterizedby high LDL-c levels. It has been shown that lowering LDL-c is notsufficient for reducing the risk of cardiovascular disease in somepatients, particularly those with normal LDL-C levels. This populationpool is identified by the independent risk factor of low HDL-c. Theincreased risk of cardiovascular disease associated with low HDL-clevels has not yet been successfully addressed by drug therapy (i.e.currently there are no drugs on the market that are useful for raisingHDL-c). (Bisgaier, C. L.; Pape, M. E. Curr. Pharm. Des. 1998, 4, 53-70).

[0003] Syndrome X (including metabolic syndrome) is loosely defined as acollection of abnormalities including hyperinsulemia, obesity, elevatedlevels of trigycerides, uric acid, fibrinogen, small dense LDLparticles, and plasminogen activator inhibitor 1 (PAI-1), and decreasedlevels of HDL-c.

[0004] NIDDM is described as insulin resistance which in turn causesanomalous glucose output and a decrease in glucose uptake by skeletalmuscle. These factors eventually lead to impaired glucose tolerance(IGT) and hyperinsulinemia.

[0005] Peroxisome Proliferator Activated Receptors (PPARs) are ophanreceptors belonging to the steroid/retinoid receptor superfamily ofligand-activated transcription factors. See, for example Willson T. M.and Wahli, W., Curr. Opin. Chem. Biol. (1997) Vol 1 pp 235-241 andWillson T. M. et. al., J. Med. Chem (2000) Vol 43 p527-549. The bindingof agonist ligands to the receptor results in changes in the expressionlevel of MRNA's encided by PPAR target genes.

[0006] Three mammalian Peroxisome Proliferator-Activated Receptors havebeen isolated and termed PPAR-alpha, PPAR-gamma, and PPAR-delta (alsoknown as NUC1 or PPAR-beta). These PPARs regulate expression of targetgenes by binding to DNA sequence elements, termed PPAR response elements(PPRE). To date, PPRE's have been identified in the enhancers of anumber of genes encoding proteins that regulate lipid metabolismsuggesting that PPARs play a pivotal role in the adipogenic signalingcascade and lipid homeostasis (H. Keller and W. Wahli, Trends Endocrin.Metab 291-296, 4 (1993)).

[0007] It has now been reported that thiazolidinediones are potent andselective activators of PPAR-gamma and bind directly to the PPAR-gammareceptor (J. M. Lehmann et. al., J. Biol. Chem. 12953-12956, 270(1995)), providing evidence that PPAR-gamma is a possible target for thetherapeutic actions of the thiazolidinediones.

[0008] Activators of the nuclear receptor PPARγ, for exampletroglitazone, have been shown in the clinic to enhance insulin-action,reduce serum glucose and have small but significant effects on reducingserum triglyceride levels in patients with Type 2 diabetes. See, forexample, D. E. Kelly et al., Curr. Opin. Endocrnol. Diabetes, 90-96, 5(2), (1998); M. D. Johnson et al., Ann. Pharmacother., 337-348, 32 (3),(1997); and M. Leutenegger et al., Curr. Ther. Res., 403-416, 58 (7),(1997).

[0009] The mechanism for this triglyceride lowering effect appears to bepredominantly increased clearance of very low density lipoproteins(VLDL) through induction of liporotein lipase (LPL) gene expression.See, for example, B. Staels et al., Arteroscler. Thromb., Vasc. Biol.,1756-1764, 17 (9), (1997).

[0010] Fibrates are a class of drugs which may lower serum triglycerides20-50%, lower LDLc 10-15%, shift the LDL particle size from the moreatherogenic small dense to normal dense LDL, and increase HDLc 10-15%.Experimental evidence indicates that the effects of fibrates on serumlipids are mediated through activation of PPARα. See, for example, B.Staels et al., Curr. Pharm. Des., 1-14, 3 (1), (1997). Activation ofPPARα results in transcription of enzymes that increase fatty acidcatabolism and decrease de-novo fatty acid synthesis in the liverresulting in decreased triglyceride synthesis and VLDLproduction/secretion. In addition, PPARα activation decreases productionof apoC-III. Reduction in apoC-III, an inhibitor of LPL activity,increases clearance of VLDL. See, for example, J. Auwerx et al.,Atherosclerosis, (Shannon, Irel.), S29-S37, 124 (Suppl), (1996).

[0011] Certain compounds that activate or otherwise interact with one ormore of the PPARs have been implicated in the regulation of triglycerideand cholesterol levels in animal models. See, for example, U.S. Pat.Nos. 5,847,008 (Doebber et al.) and U.S. Pat. No. 5,859,051 (Adams etal.) and PCT publications WO 97/28149 (Leibowitz et al.) and WO99/04815(Shimokawa et al.). In a recent report (Berger et al., J. Biol. Chem.1999), vol. 274, pp. 67184725) K was stated that PPARδ activation doesnot appear to modulate glucose or triglyceride levels.

[0012] Accordingly, the present invention provides a compound of formula(I) and pharmaceutically acceptable salts, hydrolysable esters andsolvates thereof;

[0013] wherein

[0014] X¹ is O, S, NH or NCH₃, C₁₋₃ alkyl.

[0015] R¹ and R² are independently H or C₁₋₃ alkyl.

[0016] R³, R⁴ and R⁵ are independently H, CH₃, OCH₃, CF₃ or halogen;

[0017] R²⁶ and R²⁷ are independently H. C₁₋₃ alkyl or an R²⁶ and R²⁷may, together with the carbon atom to which they are bonded form a 3-5membered cycloalkyl ring;

[0018] m is 0-3;

[0019] X² is (CR¹⁰R¹¹)_(n), O, S, OCH₂;

[0020] n=1 or 2;

[0021] R⁶, R⁷, R¹⁰ and R¹¹ independently represent H, F, C₁₋₆alkyl,phenyl or allyl or form a double bond as indicated by the depicteddashed line;

[0022] one of Y and Z is CH, the other is S or O with the proviso that Ycannot be substituted and Z can only be substituted when it is carbon.

[0023] R⁸ is phenyl or pyridyl (wherein the N is in position 2 or 3)either of which may optionally be substituted by one or more halogen,CF₃, OCF₃, C₁₋₆ straight or branched alkyl with the provision that whenR³ is pyridyl, the N is unsubstituted.

[0024] R⁹ is C₁₋₆alkyl, CF₃ or —CH₂D, wherein D is selected from:

[0025] wherein

[0026] R¹² is selected from the group consisting of moieties depictedbelow.

[0027] R¹⁷ and R¹⁸ are independently hydrogen C₁₋₆alkyl,C₁₋₆perfluoroalkyl, C₁₋₆acyl, —OC₁₋₆alkyl, perfluoroOC₁₋₆alkyl, or1-hydroxyC₁₋₆alkyl;

[0028] R¹⁹ is C₁₋₆alkyl;

[0029] R²² is C₁₋₆alkyl, 5-membered aryl, 5-membered heteroaryl,—C₁₋₆alkylenearyl;

[0030] R²³ is C₁₋₆alkyl, C₃₋₆cycloalkyl, 6-membered aryl or a 5-memberedheteroaryl optionally substituted with one or two substituents selectedfrom perfluroC₁₋₆alkyl, perfluroOC₁₋₆alkyl, C₁₋₆alkyl, —OC₁₋₆alkyl and—SC₁₋₆alkyl; and.

[0031] R²⁴ is C₁₋₆alkyl, —C₁₋₆alkylenearylC₁₋₆alkylaryl, or a 6-memberedaryl optionally substituted with one or two substituents selected fromperfluroC₁₋₆alkyl, perfluroOC₁₋₆alkyl, C₁₋₆alkyl, —OC₁₋₄alkyl, and—SC₁₋₆alkyl;

[0032] where Z is O, N or S (note that when Z is N, the depicted bondcan be attached to the nitrogen in the ring as well as any of thecarbons in the ring);

[0033] R²⁰ is C₁₋₆alkyl, 6 membered aryl, —OC₁₋₆alkyl, hydroxy or1-alkoxy C₁₋₆alkyl.

[0034] where R¹³ and R¹⁴ are independently halogen, a 6-membered aryl ora 5-membered heteroaryl optionally substituted with one or twosubstituents selected from perfluroC₁₋₆alkyl, perfluroOC₁₋₆alkyl,C₁-alkyl, —OC₁₋₄alkyl, and —SC₁₋₆alkyl;

[0035] R²¹ is C₁₋₃alkyl, —C₁₋₆alkylenephenyl, 6 membered aryl, eachoptionally substituted with one or two substituents selected from CN,halogen 5 or 6 membered heteroaryl, bicyclic aryl or bicyclicheteroaryl, perfluroC₁₋₆alkyl, perfluroOC₁₋₆alkyl, C₁₋₆alkyl,—OC₁₋₆alkyl and SC₁₋₆alkyl.

[0036] R¹⁵ and R¹⁶ are independently C₁₋₆alkyl, C₃₋₄cycloalkyl,C₁₋₄alkylene 6-membered aryl optionally substituted with 1 or 2C₁₋₃alkyl or alkoxy groups, C₀₋₆alkylene 5-membered heteroaryl, pyridyl,bicyclic aryl or bicyclic heteroaryl or R¹² as defined above.

[0037] wherein n is 1-3, R²⁸ is 6 membered aryl, 5 or 6 memberedheteroaryl or bicyclic aryl or bicyclic heteroaryl.

[0038] wherein R²¹ is defined above.

[0039] As used herein, “aryl” or any phrase or term including aryl suchas “C₁₋₆alkylenearyl”, the “aryl” means a phenyl group or a 5 or 6membered heteroaryl group. As used herein the term “heteroaryl” means a5 or 6 membered heteroaryl group.

[0040] As used herein any such “aryl” or “heteroaryl” group mayoptionally be substituted with one or two substituents selected from thegroup consisting of halogen, CN, dimethylamino, perfluroC₁₋₆-alkyl,perfluroOC₁₋₆alkyl, C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆alkyleneOC₁₋₆alkyl, and—SC₁₋₆alkyl.

[0041] In another aspect, the present invention discloses a method forprevention or treatment of a disease or condition mediated by one ormore human PPAR alpha, gamma or delta (“hPPARs”) comprisingadministration of a therapeutically effective amount of a compound ofthis invention. hPPAR mediated diseases or conditions includedyslipidemia including associated diabetic dyslipidemia and mixeddyslipidemia, syndrome X (as defined in this application this embracesmetabolic syndrome), heart failure, hypercholesteremia, cardiovasculardisease including atherosclerosis, arteriosclerosis, andhypertriglyceridemia, type II diabetes mellitus, type I diabetes,insulin resistance, hyperlipidemia, inflammation, epithelialhyperproliferative diseases including eczema and psoriasis andconditions associated with the lung and gut and regulation of appetiteand food intake in subjects suffering from disorders such as obesity,anorexia bulimia, and anorexia nervosa. In particular, the compounds ofthis invention are useful in the treatment and prevention of diabetesand cardiovascular diseases and conditions including atherosclerosis,arteriosclerosis, hypertriglyceridemia, and mixed dyslipidaemia.

[0042] In another aspect, the present invention provides pharmaceuticalcompositions comprising a compound of the invention, preferably inassociation with a pharmaceutically acceptable diluent or carrier.

[0043] In another aspect, the present invention provides a compound ofthe invention for use in therapy, and in particular, in human medicine.

[0044] In another aspect, the present invention provides the use of acompound of the invention for the manufacture of a medicament for thetreatment of a hPPAR mediated disease or condition.

[0045] As used herein, “a compound of the invention” means a compound offormula (I) or a pharmaceutically acceptable hydrolysable ester or,solvate, thereof.

[0046] While hydrolyzable esters are included in the scope of thisinvention, the acids are preferred because the data suggests that whilethe esters are useful compounds, it may actually be the acids to whichthey hydrolyze that are the active compounds. Esters that hydrolyzereadily can produce the carboxylic acid in the assay conditions or invivo. Generally the carboxylic acid is active in both the binding andtransient transfection assays, while the ester does not usually bindwell but is active in the transient transfection assay presumably due tohydrolysis. Preferred hydrolysable esters are C₁₋₆ alkyl esters whereinthe alkyl group may be straight chain or branched chain. Methyl or ethylesters are more preferred.

[0047] Preferably R²⁶ and R²⁷ are independently H or CH₃. Morepreferably R¹ and R² are H.

[0048] Preferably m is 0

[0049] Preferably X¹ is O, S, NH, NCH₃. More preferably X¹ is O or S.

[0050] Preferably X² is (CR¹⁰R¹¹)_(n), O or S and where n is preferably1.

[0051] Preferably R⁶, R⁷, R¹⁰ and R¹¹ are H.

[0052] Preferably R⁸ is phenyl, optionally substituted by 1, 2, 3, 4 or5 substituents independently selected from CH₃, OCH₃, CF₃ or halogen.

[0053] Preferably R⁸ whether phenyl or pyridyl is mono or disubstituted.When disubstituted preferably one of the substituents is halogen, morepreferably one is halogen and the other is CF₃.

[0054] More preferably R⁸ whether phenyl or pyridyl is monosubstituted.When monosubstituted, preferably the substituent is in the para positionon the ring and is most preferably CF₃.

[0055] Preferably R³ is H, CH₃ or CF₃. More preferably, R³ is CH₃.

[0056] Preferably R⁴ and R⁵ are both H.

[0057] Preferably R⁹ is C₁-alkyl, CF₃ or CH₂D wherein D is selected frommoieties G, H, I, J and K.

[0058] When D represents moiety 1, preferably n is 1 or 2 and R²⁸ ispyridyl or optionally substituted phenyl.

[0059] When D represents moiety J or K, preferably R²¹ is C₁₋₃alkyl,C₁₋₆alkylenephenyl, a bicyclic heteroaryl group or a 5 or 6 memberedheteroaryl group.

[0060] When D represents moiety G. R¹⁵ and R¹⁶ preferably independentlyrepresent:

[0061] C₁-alkyl, C cycloalkyl, phenyl, —C₁₋₆alkylenephenyl (optionallysubstituted), —C₁-alkylenepyridyl.

[0062] While the preferred groups for each variable have generally beenlisted above separately for each variable, preferred compounds of thisinvention include those in which several or each variable in Formula (I)is selected from the preferred, more preferred, or most preferred groupsfor each variable. Therefore, this invention is intended to include allcombinations of preferred, more preferred, and most preferred groups.

[0063] Preferably, the compounds of formula (I) are hPPAR agonists. ThehPPAR agonists of formula (I) may be agonists of only one type(“selective agonists”), agonists for two PPAR subtypes (“dualagonists”), or agonists for all three subtypes (“pan agonists”). As usedherein, by “agonist”, or “activating

[0064] compound”, or “activator”, or the like, is meant those compoundswhich have a pKi of at least 6.0 preferably at least 7.0 to the relevantPPAR, for example hPPARδ? in the binding assay described below, andwhich achieve at least 50% activation of the relevant PPAR relative tothe appropriate indicated positive control in the transfection assaydescribed below at concentrations of 10⁻⁵ M or less. More preferably,the compounds of this invention achieve 50% activation of at least onehuman PPAR in the relevant transfection assay at concentrations of 10⁻⁶M or less. More preferably the compounds of the invention achieve 50%activation of at least one human PPAR in the relevant transfection assayat concentrations of 10⁻⁷M or less.

[0065] Preferred compounds of the invention include

[0066]{4-[({3-ethyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]-2-methylphenoxy}aceticacid

[0067][4-({[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]methyl}thio)-2-methylphenoxy]aceticacid

[0068][2-methyl-4-({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)phenoxy]aceticacid

[0069]{2-methyl-4-[({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid

[0070]{2-methyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[0071]{2-ethyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[0072]{2-isopropyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[0073][2-methyl-4-({3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methoxy)phenoxy]aceticacid

[0074]{4-[({2-[(benzylthio)methyl]-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid

[0075]{2-methyl-4-[({3-methyl-5-[4-(trifluoromethyl)phenyl]-2-furyl}methyl)thio]phenoxy}aceticacid

[0076]{2-methyl-4-[({3-methyl-4-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid

[0077][4-({[5-(4-chlorophenyl)-2-methyl-3-furyl]methyl}thio)-2-methylphenoxy]aceticacid

[0078]{2-methyl-4-[({2-(trifluoromethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[0079][2-methyl-4-(2-{4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}ethyl)phenoxy]aceticacid

[0080][2-methyl-4-(2-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethyl)phenoxy]aceticacid

[0081](4-{2-[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]ethyl}-2-methylphenoxy)aceticacid

[0082]3-[4-({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)phenyl]propanoicacid

[0083]{2-methyl-4-[({3-(phenoxymethyl)-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid

[0084]3-[2-methyl-4-({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)phenyl]propanoicacid

[0085]{4-[({2-[(benzylthio)methyl]-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid

[0086]{4-[({2-[(isopropylthio)methyl]-5-[4-(trifluoromethyl)phenyl]-3-furyl)methyl)thio]-2-methylphenoxy}aceticacid

[0087]{2-methyl-4-[({2-[methyl(phenyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[0088][2-methyl-4-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)phenoxy]aceticacid

[0089]3-[2-methyl-4-(2-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethyl)phenyl]propanoicacid

[0090][2-methyl-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]thien-3-yl}methoxy)phenoxy]aceticacid

[0091]{4-[({2-isopentyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid

[0092]{2-methyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]thien-3-yl}methyl)thio]phenoxy}aceticacid

[0093][4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-(trifluoromethyl)phenoxy]aceticacid

[0094]{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[0095]{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-2-furyl}methyl)thio]phenoxy}aceticacid

[0096]{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]thien-3-yl}methyl)thio]phenoxy}aceticacid

[0097]{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid

[0098][4-({[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]methyl}thio)-2-methylphenoxy]aceticacid

[0099](4-{[5-(4-chlorophenyl)-2-methyl-3-furyl]methoxy}-2-methylphenoxy)aceticacid

[0100][2-methyl-4-({2-(trifluoromethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenoxy]aceticacid

[0101][2-methyl-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenoxy]aceticacid

[0102][2-methyl-4-({3-methyl-5-[4-(trifluoromethyl)phenyl]-2-furyl)methoxy)phenoxy}aceticacid

[0103]3-(4-{5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]methoxy}phenyl)propanoicacid

[0104](4-{[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]methoxy}-2-methylphenoxy)aceticacid

[0105][4-({[5-(4-chlorophenyl)-2-methyl-3-furyl]methyl}thio)-2-(trifluoromethyl)phenoxy]aceticacid

[0106]{4-[({3-[(isopropylthio)methyl]-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]-2-methylphenoxy}aceticacid

[0107]{4-[({3-[(benzylthio)methyl]-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]-2-methylphenoxy}aceticacid

[0108]3-(4-{[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]methoxy}-2-methylphenyl)propanoicacid

[0109] {2-methyl-4-[({2-(phenoxymethyl)-5-[4-(trifluoromethyl)phenyl]-3furyl}methyl)thio]phenoxy}acetic acid

[0110]3-[2-methyl-4-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)phenyl]propanoicacid

[0111]{2-methyl-4-[({3-{[4-(trifluoromethyl)phenoxy]methyl}-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid

[0112]{4-[({2-{[(2-furylmethyl)thio]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid

[0113]{2-methyl-[({2-[2-(4-methylphenyl)ethyl]-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[0114]{4-[({2{[(2,4-difluorophenyl)thio]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl)methyl)thio]-2-methylphenoxy}aceticacid

[0115]{4-[({2{[(3,5-dimethylphenyl)thio]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid

[0116]{4-[({2{[(4-tert-butylphenyl)thio]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid

[0117]{2-methyl-4-[({3-{[methyl(phenyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid

[0118]{2-methyl-4-[({2-(2-pyridin-4-ylethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid hydrochloride

[0119]{4-[({2-isobutyl-5-[4-(trifluoromethyl)phenyl]3-furyl}methyl)thio]-2-methylphenoxy}aceticacid

[0120]{2-methyl-4-[({2{[methyl(pyridin-3-yl}methyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid hydrochloride

[0121]{4-[({2{[cyclohexyl(methyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid hydrochloride

[0122]{2-methyl-4-[({2{[methyl(2-phenylethyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid hydrochloride

[0123][2-methyl-4-(1-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethoxy)phenoxy]aceticacid

[0124][4-({3-[(isopropylthio)methyl]-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)-2-methylphenoxy]aceticacid

[0125][2-methyl-4-(1-{5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethoxy)phenoxy]aceticacid

[0126][2-methyl-4-(1-{5-[4-(trifluoromethyl)phenyl]thien-3-yl}ethoxy)phenoxy]aceticacid

[0127][2-methyl-4-(phenyl{5-[4-(trifluoromethyl)phenyl]thien-3-yl}methoxy)phenoxy]aceticacid

[0128]2-methyl-2-[2-methyl-4-(phenyl{5-[4-(trifluoromethyl)phenyl]thien-3-yl}methoxy)phenoxy]propanoicacid

[0129]{2-methyl-4-[({3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl)methyl)thio]phenoxy}aceticacid

[0130][4-({5-[2,5-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)-2-methylphenoxy]aceticacid

[0131][4-({5-[2,3-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)-2-methylphenoxy]aceticacid

[0132][2-methyl-4-({3-methyl-5-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]thien-2-yl}methoxy)phenoxy]aceticacid

[0133][4-({5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)-2-methylphenoxy]aceticacid

[0134] More Preferred:

[0135]{2-methyl-4-[({3-methyl-5-[4-(trifluoromethyl)phenyl)-2-furyl}methyl)thio]phenoxy}aceticacid

[0136]{2-methyl-4-[({3-methyl-4-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid

[0137][4-({[5-(4-chlorophenyl)-2-methyl-3-furyl]methyl}thio)-2-methylphenoxy]aceticacid

[0138]{2-methyl-4-[({2-(trifluoromethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[0139][2-methyl-4-(2-4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}ethyl)phenoxy]aceticacid

[0140][2-methyl-4-(2{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethyl)phenoxy]aceticacid

[0141]{4-2-[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]ethyl)₂-methylphenoxy}aceticacid

[0142]3-[4-({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)phenyl]propanoicacid

[0143]{2-methyl-4-[({3-(phenoxymethyl)-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid

[0144]3-[2-methyl-4-({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)phenyl]propanoicacid

[0145]{4-[({2-[(benzylthio)methyl]-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid

[0146]{4-[({2-[(isopropylthio)methyl]-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid

[0147]{2-methyl-4-[({2{[methyl(phenyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[0148][2-methyl-4-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)phenoxy]aceticacid

[0149]3-[2-methyl-4-(2{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethyl)phenyl]propanoicacid

[0150][2-methyl-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]thien-3-yl}methoxy)phenoxy]aceticacid

[0151]{4-[({2-isopentyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid

[0152]{2-methyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]thien-3-yl}methyl)thio]phenoxy}aceticacid

[0153][4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-(trifluoromethyl)phenoxy]aceticacid

[0154] Particularly preferred compounds are

[0155]{4-[({3-ethyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]-2-methylphenoxy}aceticacid

[0156][4-({[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]methyl}thio)-2-methylphenoxy]aceticacid

[0157][2-methyl-4-({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)phenoxy]aceticacid

[0158]{2-methyl-4-[({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid

[0159]{2-methyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl)methyl)thio]phenoxy}aceticacid

[0160]{2-ethyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[0161]{2-isopropyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[0162][2-methyl-4-({3-methyl-5[4-(trifluoromethoxy)phenyl]thien-2-yl}methoxy)phenoxy]aceticacid

[0163]{4-[({2-[(benzylthio)methyl]-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid

[0164] It will also be appreciated by those skilled in the art that thecompounds of the present invention may also be utilized in the form of apharmaceutically acceptable salt or solvate thereof. The physiologicallyacceptable salts of the compounds of formula (I) include conventionalsalts formed from pharmaceutically acceptable inorganic or organic acidsor bases as well as quaternary ammonium acid addition salts. Morespecific examples of suitable acid salts include hydrochloric,hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic,propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric,palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic,salicylic, fumaric, toluenesulfonic, methanesulfonic,naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic,malic, steroic, tannic and the like. Other acids such as oxalic, whilenot in themselves pharmaceutically acceptable, may be useful in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable salts. Morespecific examples of suitable basic salts include sodium, lithium,potassium, magnesium, aluminium, calcium, zinc,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, N-methylglucamine and procaine salts. Those skilled inthe art of organic chemistry will appreciate that many organic compoundscan form complexes with solvents in which they are reacted or from whichthey are precipitated or crystallized. These complexes are known as“solvents”. For example, a complex with water is known as a “hydrate”.Solvates of the compound of formula (I) are within the scope of theinvention. References hereinafter to a compound according to theinvention include both compounds of formula (I) and theirpharmaceutically acceptable salts and solvates.

[0165] The compounds of the invention and their pharmaceuticallyacceptable derivatives are conveniently administered in the form ofpharmaceutical compositions. Such compositions may conveniently bepresented for use in conventional manner in admixture with one or morephysiologically acceptable carriers or excipients.

[0166] While it is possible that compounds of the present invention maybe therapeutically administered as the raw chemical, it is preferable topresent the active ingredient as a pharmaceutical formulation. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not deleterious to therecipient thereof.

[0167] Accordingly, the present invention further provides for apharmaceutical formulation comprising a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof together with one ormore pharmaceutically acceptable carriers therefore and, optionally,other therapeutic and/or prophylactic ingredients.

[0168] The formulations include those suitable for oral, parenteral(including subcutaneous e.g. by injection or by depot tablet,intradermal, intrathecal, intramuscular e.g. by depot and intravenous),rectal and topical (including dermal, buccal and sublingual)administration although the most suitable route may depend upon forexample the condition and disorder of the recipient. The formulationsmay conveniently be presented in unit dosage form and may be prepared byany of the methods well known in the art of pharmacy. All methodsinclude the step of bringing into association the compounds (“activeingredient”) with the carrier which constitutes one or more accessoryingredients. In general the formulations are prepared by uniformly andintimately bringing into association the active ingredient with liquidcarriers or finely divided solid carriers or both and then, ifnecessary, shaping the product into the desired formulation.

[0169] Formulations suitable for oral administration may be presented asdiscrete units such as capsules, cachets or tablets (e.g. chewabletablets in particular for paediatric administration) each containing apredetermined amount of the active ingredient; as a powder or granules;as a solution or a suspension in an aqueous liquid or a non-aqueousliquid; or as an oil-in-water liquid emulsion or a water-in-oil liquidemulsion. The active ingredient may also be presented as a bolus,electuary or paste.

[0170] A tablet may be made by compression or moulding, optionally withone or more accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with aother conventional excipients such as binding agents, (for example,syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch orpolyvinylpyrrolidone), fillers (for example, lactose, sugar,microcrystalline cellulose, maize-starch, calcium phosphate orsorbitol), lubricants (for example, magnesium stearate, stearic acid,talc, polyethylene glycol or silica), disintegrants (for example, potatostarch or sodium starch glycollate) or wetting agents, such as sodiumlauryl sulfate. Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein. The tablets may be coated according to methodswell-known in the art.

[0171] Alternatively, the compounds of the present invention may beincorporated into oral liquid preparations such as aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, for example.Moreover, formulations containing these compounds may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may contain conventional additives such assuspending agents such as sorbitol syrup, methyl cellulose,glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats;emulsifying agents such as lecithin, sorbitan mono-oleate or acacia;non-aqueous vehicles (which may include edible oils) such as almond oil,fractionated coconut oil, oily esters, propylene glycol or ethylalcohol; and preservatives such as methyl or propyl p-hydroxybenzoatesor sorbic acid. Such preparations may also be formulated assuppositories, e.g., containing conventional suppository bases such ascocoa butter or other glycerides.

[0172] Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

[0173] The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored ina freeze-dried (lyophilised) condition requiring only the addition of asterile liquid carrier, for example, water-for-injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions may beprepared from sterile powders, granules and tablets of the kindpreviously described.

[0174] Formulations for rectal administration may be presented as asuppository with the usual carriers such as cocoa butter, hard fat orpolyethylene glycol.

[0175] Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavoured basis such as sucrose and acacia ortragacanth, and pastilles comprising the active ingredient in a basissuch as gelatin and glycerin or sucrose and acacia.

[0176] The compounds may also be formulated as depot preparations. Suchlong acting formulations may be administered by implantation (forexample subcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, the compounds may be formulated withsuitable polymeric or hydrophobic materials (for example as an emulsionin an acceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

[0177] In addition to the ingredients particularly mentioned above, theformulations may include other agents conventional in the art havingregard to the type of formulation in question, for example thosesuitable for oral administration may include flavouring agents.

[0178] It will be appreciated by those skilled in the art that referenceherein to treatment extends to prophylaxis as well as the treatment ofestablished diseases or symptoms. Moreover, it will be appreciated thatthe amount of a compound of the invention required for use in treatmentwill vary with the nature of the condition being treated and the age andthe condition of the patient and will be ultimately at the discretion ofthe attendant physician or veterinarian. In general, however, dosesemployed for adult human treatment will typically be in the range of0.02-5000 mg per day, preferably 1-1500 mg per day. The desired dose mayconveniently be presented in a single dose or as divided dosesadministered at appropriate intervals, for example as two, three, fouror more sub-doses per day. The formulations according to the inventionmay contain between 0.1-99% of the active ingredient, conveniently from30-95% for tablets and capsules and 3-50% for liquid preparations.

[0179] The compound of formula (I) for use in the instant invention maybe used in combination with other therapeutic agents for example,statins and/or other lipid lowering drugs for example MTP inhibitors andLDLR upregulators. The compounds of the invention may also be used incombination with antidiabetic agents, e.g. mefformin, sulfonylureasand/or PPAR gamma, PPAR alpha or PPAR alpha/gamma agonists (for examplethiazolidinediones such as e.g. Pioglitazone and Rosiglitazone). Thecompounds may also be used in combination with antihypertensive agentssuch as angistensin antagonists e.g. telmisartan, calcium channelantagonists e.g. lacidipine and ACE inhibitors e.g. enalapril. Theinvention thus provides in a further aspect the use of a combinationcomprising a compound of formula (I) with a further therapeutic agent inthe treatment of a hPPAR mediated disease.

[0180] When the compounds of formula (I) are used in combination withother therapeutic agents, the compounds may be administered eithersequentially or simultaneously by any convenient route.

[0181] The combinations referred to above may conveniently be presentedfor use in the form of a pharmaceutical formulation and thuspharmaceutical formulations comprising a combination as defined aboveoptimally together with a pharmaceutically acceptable carrier orexcipient comprise a further aspect of the invention. The individualcomponents of such combinations may be administered either sequentiallyor simultaneously in separate or combined pharmaceutical formulations.

[0182] When combined in the same formulation it will be appreciated thatthe two compounds must be stable and compatible with each other and theother components of the formulation and may be formulated foradministration. When formulated separately they may be provided in anyconvenient formulation, conveniently in such a manner as are known forsuch compounds in the art.

[0183] When a compound of formula (I) is used in combination with asecond therapeutic agent active against the same hPPAR mediated disease,the dose of each compound may differ from that when the compound is usedalone. Appropriate doses will be readily appreciated by those skilled inthe art.

[0184] The compounds of the invention may be prepared by one of thefollowing routes:

[0185] (a) Coupling of a thiol or phenol (A) and a heterocyclic methanol(B), by the Mitsonobu reaction (O. Mitsunobu, Synthesis, 1981, 1) or byreaction of the thiol or phenol (A) with a heterocyclic methyl halide(eg chloride) prepared from the methanol (B), followed by hydrolysis ofthe ester R₁₀

[0186] or a further modification is to use a sulfonyl chloride, which isreduced and coupled in situ with a heterocyclic methanol.

[0187] Intermediates A can be prepared as follows; where X₂═SO₂Cl, bydirect sulfonation of an aromatic precursor such as commerciallyavailable ester C (A. Badawi et al, Pharmazie, 1983, 38(12), 83841). Theester C may also be prepared from commercially available phenol byalkylation with ethyl bromoacetate. Where X₂═SH these compounds can beprepared by reduction of the sulfonyl chlorides (H. Uchiro et al,Tetrahedron Lett. (1999), 40(16), 3179-3182).

[0188] Where X₂═OH a commercially available phenol, such as E, isalkylated, and then reacted with a peracid such as meta chloroperbenzoicacid (mCPBA) to give an acetyl ester which is finally hydrolysed to givethe product.

[0189] The intermediate alcohols B may be prepared by one of thefollowing general routes:

[0190] i) Reduction of a commercially available acid using a reducingagent such as borane:

[0191] ii) Bromination of a known/commercially available heterocyclicester or aldehyde, followed by Suzuki coupling of the resulting bromidewith a boronic acid and then reduction:

[0192] iii) The Suzuki coupling of a protected heterocyclic boronateester, prepared by the orthometallation of a heterocyclic ring with astrong base such as butyllithium followed by quenching with analkoxyborane, with commercially available aryl bromide followed bysubsequent removal of the protecting group, such as a silyl ether.

[0193] iv) Alkylation of heterocyclic aldehydes or ketones usingorganometallic reagents, the general methods for preparation of whichare described elsewhere

[0194] v) The heterocyclic ring may be constructed by the followingprocedure

[0195] vi) Where R₉ is a more complex substituent (not methyl) this canbe introduced by reacting a compound in which R₉ is methyl with abrominating agent to give F which can be converted to the desiredmethanol by one of two methods:

[0196] by reacting with a nucleophilic group R₁₁ (R₁₁ can be a thiol,amine, alcohol or an organometallic reagent such as an organocuprate)followed by reduction of the ester gives the desired methanol.

[0197] by reaction of the bromomethyl group to give a phosphorousreagent (such as a phosphonium salt) and reaction of this with a ketoneor aldehyde. Hydrogenation followed by reduction of the ester gives thedesired methanol.

[0198] (i) Introduction of R₉ by directed metallation:

[0199] (b) Wittig (or related phosphorous reagent chemistry)

[0200] When X₁═C the bond between X₁ and the adjacent carbon may besingle or double—where it is double it is removed in the hydrogenationstep. Intermediates H are prepared by oxidation of the methanolsdescribed above. Intermediates G can be prepared can be prepared from acompound such as a commercially available ester C by treatment withformaldehyde and hydrochloric acid (Org. React. 1942, 1, 303) to givechloride I followed by reaction with triphenylphosphine.

[0201] (c) By reaction of a bromide J with an organometallic reagentsuch as a boronic acid. There is hydrolysis of a base labile esterduring the reaction.

[0202] Bromides J are prepared by the Mitsonobu reaction as described insection (a) from intermediates A and B, where B is an alcoholsynthesized from commercially available starting materials usingstandard chemical methods.

[0203] (d) By reaction of an organometallic species (K) with an arylbromide

[0204] Intermediate K is prepared as described in section (a),intermediates B are prepared by routes analogous to that describedbelow:

[0205] A protected aldehyde eg L is reacted with strong base such asn-butyl lithium followed by tributyltin chloride. Hydrolysis, followedby reduction gives the desired alcohol

[0206] (f) By alkylation of an intermediate N and subsequent hydrolysis

[0207] preparation of N eg X₁=O; X₂═CH₂

[0208] The alcohol B, prepared from known ester (see above), isconverted to the bromide and then to the phophonate (Org. React., 1951,6, 273), which reacts with the known benzaldehyde in the presecence ofbase, to give alkene O, reduction using hydrogen over a palladiumcatalyst gives N.

[0209] (g) by reaction of a halide P with a nucleophile reagent such asan amino ester with a palladium catalyst, where X₁═NHR

[0210] Intermediate P can be prepared as described in section (a)starting from a halide such as R

[0211] (h) By reaction of an organometallic species (S) with an arylbromide.

[0212] Intermediate S can be prepared as shown in the scheme below

[0213] T can be prepared as outlined in the schemes above by Wittig orrelated phoshorus chemistry.

[0214] Intermediate Y may also be prepared by the following procedure tointroduce alkyl groups (R₁₀;R₁₁═Me); The ketone X is prepared byFriedel-Crafts acylation of the thiophene U with the acid V. X may bedialkylated by using a strong non-nucleophilic base such as sodiumhydride followed by quenching the enolate with alkyl iodides. Removal ofthe methyl ether followed by alkylation with ethyl bromoacetatefurnishes ketone Y which may be reduced to the ester Z withtriethylsilane and trifluoroacetic acid.

[0215] The invention is further illustrated by the following Exampleswhich should not be construed as constituting a limitation thereto.

[0216] General Purification and Analytical Methods

[0217] Analytical HPLC was conducted on a Supelcosil LCABZ+PLUS column(3.3 cm×4.6 mm ID) eluting with 0.1% HCO₂H and 0.01 M ammonium acetatein water (solvent A), and 0.05% HCO₂H 5% water in acetonitrile (solventB), using the following elution gradient 0-0.7 minutes 0% B, 0.74.2minutes 100% B, 4.2-5.3 minutes 0% B, 5.3-5.5 minutes 0% B at a flowrate of 3 ml/minutes. The mass spectra (MS) were recorded on a Fisons VGPlatform spectrometer using electrospray positive [(ES+ve to give MH⁺and M(NH₄)⁺ molecular ions] or electrospray negative [(ES−ve to give(M−H)⁻ molecular ion] modes.

[0218]¹H nmr spectra were recorded using a Bruker DPX 400 MHzspectrometer using tetramethylsilane as the external standard.

[0219] Biotage chromatography refers to purification carried out usingequipment sold by Dyax Corporation (either the Flash 40i or Flash 150i)and cartridges pre-packed with KPSil.

[0220] Mass directed autoprep refers to methods where the material waspurified by high performance liquid chromatography on a HPLCABZ+5 μmcolumn (5 cm×10 mm i.d.) with 0.1% HCO₂H in water and 95% MeCN, 5% water(0.5% HCO₂H) utilising gradient elution at a flow rate of 8 mlminutes⁻¹. The Gilson 202-fraction collector was triggered by a VGPlatform Mass Spectrometer on detecting the mass of interest.

[0221] Hydrophobic frits refers to filtration tubes sold by Whatman.

[0222] SPE (solid phase extraction) refers to the use of cartridges soldby International Sorbent Technology Ltd.

[0223] TLC (thin layer chromatography) refers to the use of TLC platessold by Merck coated with silica gel 60 F₂₅₄.

[0224] Preparation of Intermediates:

[0225] Intermediate 1:

[0226] ethyl[2-(trifluoromethyl)phenoxy]acetate

[0227] A mixture of 2-trifluoromethylphenol (1.62 g) in anhydrousacetonitrile was treated with cesium carbonate (3.25 g) and ethylbromoacetate (1.75 g) and the reaction mixture stirred at roomtemperature for 2 hours. The reaction mixture was diluted with water andethyl acetate and the organic layer washed with water and dried withbrine and over sodium sulfate. Evaporation of ethyl acetate gave thetitle compound as a colourless oil.

[0228]¹H NMR (CDCl₃) 7.60 (d, 1H), 7.47 (t, 1H), 7.06 (t, 1H), 6.88 (d,1H), 4.72 (s, 2H), 6.55 (s, 1H), 4.26 (q, 2H), 1.29 (t, 3H).

[0229] Intermediate-2:

[0230] ethyl[4-(chlorosulfonyl)-2-methylphenoxy]acetate

[0231] Ethyl(2-methylphenoxy)acetate (0.5 g) was added to cooledchlorosulphonic acid (2 ml) at 0° C. The mixture was stirred with icecooling for 30 minutes, then allowed to warm to ambient temperature andstirred for 3 hours.

[0232] The reaction mixture was then poured cautiously onto ice, and themixture allowed to stand overnight. The title compound was isolated as awhire solid by filtration.

[0233] m/z (MH⁺)=278

[0234] Intermediate 3.

[0235] ethyl[4-(chlorosulfonyl)-2-(trifluoromethyl)phenoxy]acetate

[0236] prepared from intermediate 1, in an analogous way to intermediate2,

[0237]¹H NMR (CDCl₃) 8.29 (s, 1H), 8.17 (dd, 2H), 7.04 (d, 1H), 4.88 (s,2H), 6.55 (s, 1H), 4.30 (q,2H), 1.31 (t, 3H)

[0238] Intermediate 4:

[0239] ethyl(4-mercapto-2-methylphenoxy)acetate

[0240] A solution of ethyl[4-(chlorosulfonyl)-2-methylphenoxy]acetate(intermediate 2, 18.49) in chloroform was dried by using a hydrophobicfrit and this solution was evaporated. The residue was dissolved inchloroform (125 ml) and this solution added to a mixture of zinc powder(14.4 g) and dimethyldichlorosilane (26.6 ml) in chloroform (125 ml).The mixture was cooled to 0° C. and 1,3-dimethyl-2-imidazolinone (20.6ml) added cautiously. The reaction mixture was stirred at ambienttemperature for 10 minutes and then stirred at reflux for 18 hours. Thereaction mixture was evaporated and the resulting oil filtered and thenpartitioned between diethyl ether and 2M aqueous hydrochloric acid; theorganic phase was dried with brine and over magnesium sulfate. Theproduct isolated after evaporation of the solvent was further purifiedby flash column chromatography using neat chloroform as eluent to givethe title compound as a colourless oil which solidified upon standing.

[0241] HPLC Rt=3.5 minutes

[0242] Intermediate 5:

[0243] ethyl{4-acetyl-2-methylphenoxy)acetate

[0244] 1-(4-Hydroxy-3-methylphenyl)ethanone (90 g) and cesium carbonate(216 g) were stirred in acetonitrile (900 ml) at room temperature undernitrogen for 10 minutes. Ethyl bromoacetate (73 ml) was added and themixture heated to 40° C. for 3 hours. Further ethyl bromoacetate (2.5ml) and cesium carbonate (1 g) were added and heating continued for afurther hour. The cooled reaction was filtered and the filtrateconcentrated to give the title compound as a yellow oil.

[0245] m/z (MH⁺)=237

[0246] Intermediate 6:

[0247] ethyl[4-(acetyloxy)-2-methylphenoxy]acetate

[0248] A solution of ethyl(4-acetyl-2-methylphenoxy)acetate(intermediate 5, 141 g) in dichloromethane (3000 ml) containing4-toluenesulphonic acid (13.7) was heated to 39° C. under nitrogenm-chloro perbenzoic acid (312 g) was added portionwise over 40 minutes.The mixture was stirred for a further 7 hours and then allowed to coolwith stirring overnight. Dichloromethane (1000 ml) was added and themixture filtered. The filtrate was added slowly to a solution ofpotassium iodide (750 g) in water (5000 ml) and the mixture stirred for10 minutes. The organic layer was separated and again added to asolution of potassium iodide (750 g) in water (5000 ml). After stirringfor 10 minutes the organic layer was again separated, then washed with10% aqueous sodium sulfite followed by water and brine, then dried overmagnesium sulfate, filtered and the filtrate concentrated to give thetitle compound as an orange oil.

[0249] m/z (MH⁺)=253

[0250] Intermediate 7:

[0251] ethyl(4-hydroxy-2-methylphenoxy)acetate

[0252] A solution of ethyl[4-(acetyloxy)-2-methylphenoxy}acetate(intermediate 6, 148 g) in ethanol (1300 ml) was treated with sodiumethoxide (41.3 g) and the mixture heated to 45° C. for 2.5 hours. Themixture as cooled to 22° C. and concentrated hydrochloric acid added togive a neutral (pH 7) solution. The resulting mixture was concentratedand the residue dissolved in a mixture of t-butylmethyl ether, water andbrine. The organic layer was separated, washed with brine and dried oversodium sulfate and filtered. The filtrate was concentrated to give abrown solid which was further purified by precipitation from a solutionin dichloromethane (100 ml) on addition of cyclohexane (710 ml) to givethe title compound as a brown solid.

[0253] m/z (MH⁺)=211

[0254] Intermediate 8:

[0255] ethyl 2-(4-acetyl-2-methylphenoxy)-2-methylpropanoate

[0256] A suspension of 1-(4-hydroxy-3-methylphenyl)ethanone (20.1 g) inacetonitrile (200 ml) was added to a suspension of cesium carbonate(86.6 g) in acetonitrile (400 ml) and the mixture stirred under nitrogenat room temperature for 2 minutes. ethyl 2-bromo-2-methylpropanoate (33g) was added and the mixture stirred for 25 hours, further ethyl2-bromo-2-methylpropanoate (33 g) was added and the mixture stirred fora further 16 hours. The mixture was filtered and the filtrateconcentrated to give an orange oil, the oil was dissolved in ethylacetate and the solution washed thrice with 1M sodium hydroxide andbrine. The organic layer was separated, dried over sodium sulfate,filtered and the filtrate concentrated; the resulting oil was purifiedby Biotage® chromatography eluting with cyclohexane:ethyl acetate (9:1)to give the title compound as a clear oil.

[0257] m/z (MH⁺)=265

[0258] Intermediate 9:

[0259] ethyl 2-[4-(acetyloxy)-2-methylphenoxy]-2-methylpropanoate

[0260] A solution of ethyl2-(4-acetyl-2-methylphenoxy)-2-methylpropanoate (intermediate 8, 37.33g) in dichloromethane (650 ml) was treated with 4-toluenesulphonic acid(2.75 g) followed by m-chloroperbenzoic acid (60.5 g) and the mixturewarmed to 40° C. and stirred under nitrogen for 19 hours. The cooledmixture was treated with dichloromethane (350 ml) and the resultingmixture added to aqueous potassium iodide (1000 ml, 10% solution). Theorganic layer was collected and washed twice with water and brine, thendried over sodium sulfate, filtered and the filtrate concentrated togive the title compound as an orange oil.

[0261] m/z (MH⁺)=281

[0262] Intermediate 10:

[0263] ethyl 2-(4-hydroxy-2-methylphenoxy)-2-methylpropanoate

[0264] A solution of ethyl2-[4-(acetyloxy)-2-methylphenoxy]-2-methylpropanoate (intermediate 9,40.8 g) in ethanol (280 ml) was treated with sodium ethoxide (12.9 g) atroom temperature under nitrogen. The resulting solution was heated to50° C. for 1 hour. 2M hydrochloric acid (95 ml) was added to the cooledreaction and the solution concentrated. The residue was dissolved int-butylmethyl ether and the resulting solution washed with waterfollowed by brine and then dried over sodium sulfate, filtered and thefiltrate concentrated to give a brown oil. Further purification byBiotageo® chromatography eluting initially with cyclohexane and thencyclohexane:ethyl acetate (5:1) gave the title compound as an orangeoil.

[0265] m/z(MH⁺)=239

[0266] Intermediate 11:

[0267] Ethyl 3-[4-(benzyloxy)-2-methylphenyl]prop-2-enoate

[0268] A solution of triethyl phosphonoacetate (0.88 ml) in drytetrahydrofuran (20 ml) was cooled to 0° C. and treated in smallportions with a 60% dispersion in oil of sodium hydride (0.194 g). Onceeffervescence was complete, a solution of2-methyl-4-benzyloxybenzaldehyde (1.0 g) in dry tetrahydrofuran (20 ml)was added drop-wise. The resulting solution was stirred at 0° C. for 1.5hours then the cooling bath removed and the reaction allowed to warm to210 over 2.5 hours. The reaction was then poured into ethylacetate/water and the aqueous phase separated and extracted with moreethyl acetate. The combined organic phases were washed with water,brine, dried over sodium sulfate and evaporated in vacuo. The productwas further purified by flash column chromatography usingcyclohexane:ethyl acetate (19:1) as an eluent to give the title compoundas a white solid.

[0269] HPLC Rt=4.1 minutes

[0270] Intermediate 12:

[0271] Ethyl 3-(4-hydroxy-2-methylphenyl)propanoate

[0272] A solution of ethyl 3-[4-(benzyloxy)-2-methylphenyl]prop-2-enoate(intermediate 11, 1.054 g) in ethanol (50 ml) was added to a suspensionof palladium hydroxide on carbon (0.15 g) in ethanol (5 ml) undernitrogen gas. The resulting suspension was then stirred under a hydrogenatmosphere for 3 hours. The mixture was filtered through Harborlitefilter aid and the pad washed with more ethanol. The combined filtrateswere evaporated in vacuo to give the title compound as a clear oil.

[0273] HPLC Rt=3.1 minutes.

[0274] Intermediate 13:

[0275] ethyl[4-(hydroxymethyl)-2,6-dimethylphenoxy]acetate

[0276] A solution of 4-(hydroxymethyl)-2,6-dimethylphenol (P. Claus etal., Monatsh. Chem. 1972, 103(4), 1178-1193) (1.9 g) in acetonitrile (50ml) was treated with ethyl bromoacetate (2.17 g) and caesium carbonate(4.24 g) and the mixture stirred at room temperature overnight. Thesolution was concentrated and the residue partitioned between ethylacetate and water. The organic layer was collected, dried over magnesiumsulfate and filtered. The filtrate was concentrated to give the titlecompound as a yellow oil.

[0277]¹H NMR (CDCl₃) δ 7.0 (s, 2H), 4.6 (s, 2H), 4.4 (s, 2H), 4.3 (q,2H), 2.3 (s, 6H), 1.35 (t, 3H)

[0278] Intermediate 14:

[0279][4-(2-ethoxy-2-oxoethoxy)-3,5-(dimethylbenzyl](triphenyl)phosphoniumbromide

[0280] A solution of ethyl[4-(hydroxymethyl)-2,6-dimethylphenoxy]acetate(3.0 g) in acetonitrile (100 ml) was treated with triphenylphosphinehydrobromide (4.32 g) and the mixture heated to reflux for 6 hours. Thecooled solution was concentrated and the residue triturated with diethylether (100 ml) to precipitate the title compound which was isolated byfiltration.

[0281] HPLC Rt=2.7 minutes

[0282] Intermediate 15:

[0283][3-tert-butyl-4-(2-ethoxy-2-oxoethoxy)-5-methylbenzyl](triphenyl)phosphoniumbromide

[0284] The title compound was prepared by an analogous method to thatused for the preparation of intermediate 14 starting from2-tert-butyl-4-(hydroxymethyl)-6-methylphenol (P. G McCracken et al J.Org. Chem. (1997), 62(6), 1820-1825

[0285] HPLC Rt=3.1 minutes

[0286] Intermediate 16:

[0287] ethyl[4-(chloromethyl)-2-methylphenoxy}acetate

[0288] A mixture of ethyl(2-methylphenoxy)acetate (10.0 g) in petroleumether (40-60) (24 ml) and concentrated hydrochloric acid (60 ml) wastreated with 37% aqueous formaldehyde (4.2 ml) and the bi-phasic mixturestirred rapidly for 18 hours. The reaction mixture was diluted withethyl acetate; the aqueous layer separated and the organic layer washedwith water and then dried with brine and over sodium sulfate. Theproduct isolated after evaporation of the solvent was further purifiedby flash column chromatography using cyclohexane:ethyl acetate (14:1) aseluent to give the title compound as a white solid.

[0289] m/z (M−Cl)⁺=207

[0290] Intermediate 17:

[0291] [4-(2-ethoxy-2-oxoethoxy)-3-methylbenzyl](triphenyl)phosphoniumchloride

[0292] A mixture of[4-(2-ethoxy-2-oxoethoxy)-3-methylbenzyl](triphenyl)phosphonium chloride(intermediate 16, 2.5 g) and triphenylphosphine (2.73 g) in toluene (25ml) was stirred at reflux for 68 hours. The reaction mixture was cooledand the title compound, a white solid, isolated by filtration.

[0293] m/z (M−Cl)⁺=465

[0294] Intermediate 18:

[0295] (4-bromo-3-methylphenyl)methanol

[0296] A solution of methyl-4-bromo-3-methylbenzoate (4.31 g) in drytetrahydrofuran (20 ml) was stirred and cooled to 0° C. under nitrogengas. A solution of 1.5M diisobutylaluminium hydride in toluene (44 ml)was added slowly and the reaction stirred for 2.5 hours, then quenchedwith methanol and allowed to warm to 21° C. Silica was added and thereaction concentrated in vacuo and purified using SPE (Si cartridge)using cyclohexane:ethyl acetate (3:1) as an eluent which furnished thetitle compound as a brown oil.

[0297] HPLC Rt=3.1 minutes

[0298] Intermediate 19:

[0299] Ethyl(2E)-3-[4-hydroxymethyl)-2-methylphenyl]prop-2-enoate

[0300] A solution of (4-bromo-3-methylphenyl)methanol (intermediate 18,1.319 g) in dry dimethylformamide (15 ml) and triethylamine (7 ml) wasstirred at 21° C. under nitrogen gas and treated with ethyl acrylate(0.7 ml), (trisdibenzylideneacetone) dipalladium (0) (0.6 g) andtri(o-tolyl)phosphine (2.0 g). The resulting brown solution was stirredand heated at 80° C. for 2 hours. The reaction was allowed to cool andpoured into 2M aqueous sodium carbonate/ethyl acetate. The organic phasewas separated and washed with more sodium carbonate. The combinedaqueous phases were extracted with more ethyl acetate and the combinedorganic solution was washed with brine, dried over sodium sulfate andevaporated in vacuo. The isolated product was further purified by flashcolumn chromatography using cyclohexane:ethyl acetate (3:1) as an eluentwhich gave the title compound as a yellow oil.

[0301] HPLC Rt=3.1 minutes

[0302] Intermediate 20:

[0303] Ethyl(2E)-3-[4-(bromomethyl)-2-methylphenyl]prop-2-enoate

[0304] A solution ofethyl(2E)-3-[4-(hydroxymethyl)-2-methylphenyl]prop-2-enoate(intermediate 19, 1.389 g) in dry dichloromethane (40 ml) was cooled to0° C. and treated with carbon tetrabromide (2.3 g) followed by, in smallportions, triphenylphosphine (1.82 g). The resulting solution wasstirred thus overnight, then poured into dichloromethane/water and theorganic phase separated and washed with more water, brine and dried oversodium sulfate then evaporated in vacuo. The isolated product wasfurther purified by flash column chromatography using cyclohexane:ethylacetate (9:1) as an eluent which gave the title compound as a whitesolid.

[0305] HPLC Rt=3.8 minutes.

[0306] Intermediate 21:

[0307]{4[(1E)-3-ethoxy-3-oxoprop-1-enyl]-3-methylbenzyl}(triphenyl)phosphoniumbromide.

[0308] A solution ofethyl(2E)-3-[4-(bromomethyl)-2-methylphenyl]prop-2-enoate (intermediate20, 1.494 g) in toluene (30 ml) was stirred and treated withtriphenylphosphine (1.52 g) and then heated at reflux for 2 hours thenat 21° C. overnight. More triphenylphosphine (0.5 g) was then added andthe reaction heated at reflux for a further 5 hours. The mixture wasthen allowed to cool and filtered to give the title compound as a whitesolid.

[0309] HPLC Rt=3.0 minutes.

[0310] Intermediate 22:

[0311] methyl 5-bromo-2-methyl-3-furoate

[0312] Bromine (2.0 ml) was added drop-wise to a mixture of methyl2-methyl-3-furancarboxylate (5.0 g) in 1,4-dioxane (35 ml) stirred at 0°C. Stirring was continued at 0° C. for 2 hours and then at ambienttemperature for 18 hours. Saturated aqueous sodium thiosulfate was addedto the reaction mixture which was then extracted with ethyl acetate. Theorganic layer was dried with brine and over magnesium sulfate. Theproduct isolated after evaporation of the solvent was further purifiedby flash column chromatography using cyclohexane:ethyl acetate (19:1) aseluent to give the title compound as a yellow oil.

[0313] HPLC Rt=3.3 min

[0314] Intermediate 23:

[0315] methyl 2-methyl-5-[4-trifluoromethyl)phenyl]-3-furoate

[0316] To a solution of methyl 5-bromo-2-methyl-3-furoate (intermediate22, 0.7 g) and 4-trifluoromethylbenzene boronic acid (0.64 g,) inethyleneglycol dimethyl ether (15 ml) was added sodium carbonate (0.84g), tetrakis(triphenylphosphine)palladium (0) (0.130 g) and water (7.5ml). The mixture was heated at reflux under nitrogen. After 3 hours thereaction was allowed to cool and was concentrated. The residue waspartitioned between water and ethyl acetate; the organic solution wastaken and were dried with brine and over MgSO₄, and concentrated. Theproduct isolated after evaporation of the solvent was further purifiedby flash column chromatography using cyclohexane:ethyl acetate (14:1) aseluent to give the title compound as a white solid.

[0317] HPLC Rt=4.0 minutes

[0318] Intermediate 24:

[0319] {2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol

[0320] A solution of methyl2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furoate (intermediate 23, 0.27g) in tetrahydrofuran (10 ml) stirred at 0° C. under a nitrogenatmosphere was treated with 1M lithium aluminium hydride in ether (1.0ml). The reaction mixture was stirred at this temperature for 4 hoursand then water (2 ml) and 2M aqueous sodium hydroxide (2 ml) added. Thereaction mixture was further diluted with water; extracted with ethylacetate and the organic solution extracted with water and dried withbrine and over sodium sulfate and concentrated. The product isolatedafter evaporation of the solvent was further purified by Biotage™chromatography using a mixture of petroleum ether:ethyl acetate (1:1) aseluent to give the title compound as a white solid.

[0321] HPLC Rt=3.6 minutes

[0322] Intermediates 25-29

[0323] The following intermediates were prepared by methods analogous tothose described for the preparation of intermediate 24.

[0324] Intermediate 25:

[0325] {3-methyl-5-[4-(trifluoromethyl)phenyl]-2-furyl}methanol

[0326] Prepared from methyl 5-bromo-2-methyl-3-furoate (D. W Knight et.al., J. Chem. Soc. Perkin Trans. 11981, (3) 679-683

[0327]¹H NMR (CDCl₃) δ 7.8 (d, 2H), 7.6 (d, 2H), 6.6 (s, 1H), 4.6 (s,2H), 2.1 (s, 3H)

[0328] Intermediate 26:

[0329] {5-[4-(trifluoromethyl)phenyl]-2-furyl}methanol

[0330] Prepared from commercially available methyl 5-bromo-2-furoate.

[0331] HPLC Rt=3.3 minutes

[0332] Intermediate 27:

[0333] {5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol

[0334] Prepared from 5-bromo-3-furancarboxylic acid, methyl ester (G.Johansson et al J. Med. Chem. 1997, 40(23), 3804-3819)

[0335] HPLC Rt=3.4 minutes

[0336] Intermediate 28:

[0337] {5-[4-(trifluoromethyl)phenyl]thien-2-yl}methanol

[0338] Prepared from commercially available5-bromo-2-thiophenecarboxaldehyde.

[0339] HPLC Rt=3.6 minutes

[0340] Intermediate 29:

[0341] {5-[4-(trifluoromethyl)phenyl]thien-3-yl}methanol

[0342] Prepared from commercially available5-bromo-3-thiophenecarboxaldehyde (via intermediate 37)

[0343] HPLC Rt=3.6 minutes

[0344] Intermediate 30:

[0345] 5-(4-chlorophenyl)-3-hydroxymethyl-2-trifluoromethylfuran

[0346] A mixture of5-(4-chlorophenyl)-2-(trifluoromethyl)furan-3-carboxylic acid (0.30 g)in tetrahydrofuran (10 ml) stirred under a nitrogen atmosphere at 0° C.was treated with a 1M solution of borane in tetrahydrofuran (10.33 ml)and the reaction stirred at room temperature for 2 hours. The reactionwas cooled to 0° C.; treated with methanol (4 ml) and after 15 minutesthe reaction mixture was evaporated. The residue was purified by SPE (Sicartridge) sequentially using dichloromethane, chloroform andchloroform:ether (9:1) as eluents to give the title compound as a whitesolid.

[0347] HPLC Rt=3.8 minutes

[0348] Intermediates 31 and 32 were prepared by an analogous method tothat used to prepare intermediate 30

[0349] Intermediate 31:

[0350]{2-(trifluoromethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol

[0351] Prepared from commercially available5-(4-trifluoromethylphenyl)-2-(trifluoromethyl)furan-3-carboxylic acid

[0352] HPLC Rt=3.8 minutes

[0353] Intermediate 32:

[0354] {2-methyl-5-[4-chlorophenyl]-3-furyl}methanol

[0355] Prepared from commercially available5-(4-chlorophenyl)-2-methylfuran-3-carboxylic acid

[0356] HPLC Rt=3.5 minutes

[0357] Intermediate 33

[0358] 3-(dimethylamino)-1-[4-(trifluoromethyl)phenyl]but-2-en-1-one

[0359] A mixture of 4′-(trifluoromethyl)acetophenone (9.8 g) andN-(1,1-dimethoxyethyl)-N,N-dimethylamine (8.2 g) was heated at 112° C.overnight, under nitrogen. The reaction mixture was cooled andconcentrated giving an orange solid. Trituration with diethyl ether gavethe title compound as a yellow solid

[0360]¹H NMR (CDCl₃) δ 7.9 (d, 2H), 7.6 (d, 2H), 5.6 (s, 1H), 3.1 (s,6H), 2.7 (s, 3H)

[0361] Intermediate 34

[0362]N-{3-chloro-1-methyl-3-[4-(trifluoromethyl)phenyl]prop-2-enylidene}-N-methylmethanaminiumhexafluorophosphate

[0363] A solution of3-(dimethylamino)-1-[4-(trifluoromethyl)phenyl]but-2-en-1-one(intermediate 33, 2.6 g) in dichloromethane (25 ml) was treated withphosphorous oxychloride (1.5 g) at ambient temperature and the mixturestirred for 30 minutes. Solvent was removed in vacuo and the residuetreated with a solution of sodium hexafluorophosphate (3.4 g) inmethanol (40 ml). The title compound was isolated by filtration anddried in vacuo at ambient temperature.

[0364]¹H NMR (DMSO) δ 8.1 (d, 2H), 7.9 (d, 2H), 7.6 (s, 1H), 3.7 (s,3H), 3.6 (s, 3H), 2.7 (s, 3H)

[0365] Intermediate 35

[0366] ethyl3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate

[0367] Sodium hydride (60% dispersion in mineral oil, 0.528 g) was addedto dry ethanol (20 ml),N-{3-chloro-1-methyl-3-[4-(trifluoromethyl)phenyl]prop-2-enylidene}-N-methylmethanaminiumhexafluorophosphate (intermediate 34, 2.8 g) was added followed by ethylthioglycolate (0.79 g) and the mixture heated at 110° C. for 2 hoursunder nitrogen. The cooled mixture was concentrated in vacuo and theresidue partitioned between water and diethyl ether. The organic layerwas collected, dried over magnesium sulphate and concentrated to givethe title compound as a brown solid.

[0368]¹H NMR (CDCl₃) δ 7.7 (d, 2H), 7.6 (d, 2H), 7.2 (s, 1H), 4.3 (q,2H), 2.6 (s, 3H), 1.4 (t, 3H)

[0369] Intermediate 36:

[0370] {3-methyl-5-[4-trifluoromethyl)phenyl]thien-2-yl}methanol

[0371] A mixture of ethyl3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate(intermediate 35, 1.24 g) in tetrahydrofuran (10 ml), stirred under anitrogen atmosphere, was treated with 1M lithium aluminum hydride inether (4.5 ml) and the reaction mixture stirred at ambient temperaturefor 18 hours. The reaction mixture was treated with water (2 ml) and 2Maqueous sodium hydroxide (2 ml), diluted with water and then extractedtwice with ethyl acetate. These solutions were sequentially washed withwater, dried with brine, combined and the dried over sodium sulfate. Theproduct isolated after evaporation of the solvent was further purifiedby Biotage® chromatography using a mixture of petroleum ether ethylacetate (5:1 and 4:1) as eluents to give the title compound as a whitesolid.

[0372]¹H NMR (CDCl₃) 7.7 (d, 2H), 7.6 (d, 2H), 6.8 (s, 1H), 4.7 (d, 2H),2.5 (s, 3H), 1.8 (t, 1H).

[0373] Intermediate 37:

[0374] 4-[4-(trifluoromethyl)phenyl]thiophene-2-carbaldehyde

[0375] To a solution of 3-bromothiophene-2-carboxaldehyde (2.0 g) and3-trifluoromethylbenzene boronic acid (2.19 g) in ethylene glycoldimethyl ether (100 ml) was added sodium carbonate (2.9 g),tetrakis(triphenylphosphine) palladium (0) (0.12 g) and water (50 ml).The mixture was heated to 90° C. under nitrogen. After 18 hours thereaction was allowed to cool and was concentrated. The residue waspartitioned between water and ethyl acetate; the organic solution wastaken and was washed with brine and then dried (MgSO₄) and concentrated.The crude material was purified by SPE (Si); the product eluted withneat chloroform to furnish the title compound as a yellow solid.

[0376]¹H NMR (CDCl₃) a 10.0 (s, 1H), 8.1 (d, 1H), 7.9 (m, 1H), 7.7 (bs,4H)

[0377] Intermediate 38:

[0378] 4-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylic acid

[0379] A solution of4-[4-(trifluoromethyl)phenyl]thiophene-2-carbaldehyde (intermediate 37,1.23 g), t-butanol (20 ml) and 2-methyl-2-butene (10 ml) was cooled to0° C. To this was added drop-wise, a solution of sodium chlorite (3.8 g)and sodium dihydrogen phosphate (4.03 g) in water (15 ml). After theaddition was complete, the mixture was allowed to warm to roomtemperature and was stirred for 4 hours. The solution was thenconcentrated and partitioned between water and ethyl acetate. Theaqueous layer was washed with a second ethyl acetate portion and theorganic liquors were combined, washed with brine, then dried (MgSO₄).The solution was then absorbed onto silica and loaded onto a SPE (Si)cartridge. The product was eluted with neat ethyl acetate to afford thetitle compound as a white solid.

[0380]¹H NMR (CD₃OD) δ 8.1 (d, 1H), 8.0 (d, 1H), 7.8 (d, 2H), 7.6 (d,2H)

[0381] Intermediate 39:

[0382] N-(tert-butyl)444-(trifluoromethyl)phenyl]thiophene-2-carboxamide

[0383] A solution of 4-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylicacid (intermediate 38, 0.50 g) in thionyl chloride (4 ml) was refluxedfor 3 hours. Excess thionyl chloride was then removed in vacuo and thecrude acid chloride was dissolved in dichloromethane (20 ml) and cooledto 0° C. t-Butylamine (2.0 ml) was added slowly; the solution wasallowed to warm to room temperature and was stirred thus overnight. Themixture was then poured into 1M aqueous potassium carbonate solution andpassed through a hydrophobic frit. The concentrated product was purifiedby SPE (Si); the title compound eluted with 3:1 cyclohexane:ethylacetate.

[0384]¹H NMR (CDCl₃) δ 7.7 (d, 1H), 7.6 (s, 4H), 7.6 (d, 1H), 5.8 (bs,1H), 1.5 (s, 9H)

[0385] Intermediate 40:

[0386]N-(tert-butyl)-N,3-dimethyl-4-[4-(trifluoromethyl)phenyl]thiophene-2-carboxamide

[0387] A solution ofN-(tert-butyl)-4-[4-(trifluoromethyl)phenyl]thiophene-2-carboxamide(intermediate 39, 0.20 g) in tetrahydrofuran (50 ml) was cooled to −78°C. under nitrogen. n-Butyllithium (1.6M in hexanes, 840 μl) was addeddrop-wise and the mixture was left to stir for 30 minutes. After thistime, methyl iodide (380 μl) in tetrahydrofuran (10 ml) was added slowlyand the mixture was stirred at −78° C. for 1 hour. After this time, thereaction was allowed to warm to room temperature and was left to stirfor 24 hours. The reaction was then quenched with wet tetrahydrofuran,then water and 2M aqueous sodium hydroxide solution were added. Thetetrahydrofuran was removed in vacuo and the aqueous mixture was addedto ethyl acetate. The organic solution was taken, washed with water,brine and then was dried (magnesium sulfate) and concentrated. Thisfurnished the title compound as an off-white crystalline solid.

[0388]¹H NMR (CDCl₃) δ 7.7 (d, 2H), 7.5 (d, 2H), 7.3 (s, 1H), 3.0 (s,3H), 2.2 (s, 3H), 1.5 (s, 9H)

[0389] Intermediate 41:

[0390] {3-methyl-4-[4-(trifluoromethyl)phenyl]thien-2-yl}methanol

[0391] n-Butyllithium (1.6M in hexanes, 1.1 ml) was added dropwise to amixture of 1M diisobutylaluminium hydride in cyclohexane (1.77 ml) andtetrahydrofuran at 0° C. under nitrogen. This mixture was allowed tostir for 30 minutes then was added to a cooled (0° C.) solution ofN-(tert-butyl)-N,3-dimethyl-4-[4-(trifluoromethyl)phenyl]thiophene-2-carboxamide(intermediate 40, 0.210 g) in tetrahydrofuran (2.5 ml) under nitrogen.After 1.5 hours, a solution of sodium borohydride (0.68 g) in ethanol (5ml) was added and the reaction was allowed to warm to room temperature.After 2 hours, the reaction was quenched with wet tetrahydrofuran then2M aqueous hydrochloric acid was added and the mixture was stirred for15 minutes. Ether was added and the water layer removed. The aqueous wasextracted with 2 further portions of ether then the combined organicsolution was washed with brine then dried (MgSO₄) and concentrated. Thecrude product was purified by SPE (silica cartdrige) usingcyclohexane:ethyl acetate (3:1) as eluent to furnish the title compoundas a colourless oil.

[0392]¹H NMR (CDCl₃) δ 7.7 (d, 2H,), 7.5 (d, 2H,), 7.2 (s, 1H), 4.6 (s,2H), 2.2 (s, 3H)

[0393] Intermediate 42:

[0394] {2-methyl-5-[4-(trifluoromethyl)phenyl]thien-3-yl}methanol

[0395] This compound was prepared from 5-bromothiophene-3-carboxaldehydeby a procedure analogous to that used to prepare intermediate 41(intermediates 37-41)

[0396] HPLC Rt=3.7 minutes

[0397] Intermediate 43:

[0398] ethyl3-bromomethyl)-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate

[0399] Ethyl3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate(intermediate 35, 0.100 g) and sodium bromate (0.144 g) were suspendedin a mixture of cyclohexane and water (1:1 v/v, 4 ml). To this was addeda solution sodium bisulfite (0.99 g) in water (1 ml). The mixture wasstirred for 2 hours, quenched with 1M sodium thiosulfate solution, thenextracted with ethyl acetate. The organic layer was taken and washedwith water, sodium thiosulfate and dried with brine and over MgSO₄ andconcentrated to give the title compound as a white crystalline solid.

[0400] HPLC Rt=4.3 minutes

[0401] Intermediate 44:

[0402] methyl 2-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]-3-furoate

[0403] A solution of sodium bromate (8.14 g) in water (27 ml) wastreated with a suspension of methyl2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furoate (intermediate 23, 5.12g) in cyclohexane (36 ml). The system was cooled to <10° C. in ice/waterbath and treated with a solution of sodium hydrogen sulfite (9.4 g) inwater (54 ml) in a drop-wise manner over 30 minutes. The reaction wasallowed to warm up to 10° C. for 2 hours and then poured intodiethylether (400 ml) and washed with fresh water. The organic layer waswashed with 10% sodium thiosulfite solution and dried over magnesiumsulfate. The crude product isolated by evaporation, was pre-adsorbedonto silica and purified by flash column chromatography using 39:1cyclohexane:ethyl acetate as eluent to give the title compound as awhite powder.

[0404] HPLC Rt=4.1 minutes

[0405] Intermediate 45:

[0406] ethyl3[(benzylthio)methyl]-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate

[0407] A solution of ethyl3-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate(intermediate 43, 0.100 g) and benzyl mercaptan (0.30 g) in acetonitrile(10 ml) was treated with potassium carbonate (0.46 g) and the mixturestirred at ambient temperature overnight. The reaction mixture waspartitioned between ethyl acetate and water the organic layer ascollected, dried over magnesium sulfate and concentrated. The residuewas purified by SPE (Si cartridge) eluting initially withcyclohexane:chloroform (5:1) and then cyclohexane:chloroform (1:3) togive the title compound as a colourless oil.

[0408] HPLC Rt=4.5 minutes

[0409] Intermediate 46:

[0410]{3-[(benzylthio)methyl]-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methanol

[0411] A solution of ethyl3-[(benzylthio)methyl]-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate(intermediate 45, 0.87 g) in dry tetrahydrofuran (5 ml) was cooled to 0°C. and 1M lithium aluminium hydride solution in diethyl, ether (0.299ml) added. The reaction mixture as stirred with cooling for 3 hours.Water (0.5 ml) was added drop-wise followed by 2M hydrochloric acid (0.5ml), the further water (50 ml), the resulting mixture was extractedtwice with ethyl acetate, the extracts were combined, dried overmagnesium sulfate and concentrated. The residue was purified by SPE (Sicartridge) eluting initially with cyclohexane:chloroform (1:1) and thenchloroform to give the title compound as a white solid.

[0412] HPLC Rt=4.0 minutes

[0413] Intermediates 47-53 were prepared from intermediate 43 by methodsanalogous to those described above for the preparation of intermediate46

[0414] Intermediate 47:

[0415]{3-(phenoxymethyl)-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methanol

[0416] Prepared from intermediate 43 and phenol

[0417] HPLC Rt=3.9 minutes

[0418] Intermediate 48:

[0419]{3-[(isopropylthio)methyl]-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methanol

[0420] Prepared from intermediate 43 and isopropylthiol

[0421] HPLC Rt=4.0 minutes

[0422] Intermediate 49:

[0423]-{3-{[(4′-methyl-1,1′-biphenyl-4-yl)oxy]methyl}-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methanol

[0424] Prepared from intermediate 43 and4-hydroxy-4′-methyl-1,1′-biphenyl

[0425] HPLC Rt=4.3 minutes

[0426] Intermediate 50:

[0427]{3-{[methyl(phenyl)amino]methyl}-5-[4-trifluoromethyl)phenyl]thien-2-yl}methanol

[0428] Prepared from intermediate 43 and N— methyl aniline

[0429] HPLC Rt=3.4 minutes

[0430] Intermediate 51:

[0431]{3-{[4-(trifluoromethyl)phenoxy]methyl}-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methanol

[0432] Prepared from intermediate 43 and 4-(trifluoromethyl)phenol

[0433] HPLC Rt=4.0 minutes

[0434] Intermediate 52:

[0435]-{3-{[4-(2-phenylethyl)phenoxy]methyl}-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methanol

[0436] Prepared from intermediate 43 and 4[2-(phenylethyl)]phenol

[0437] HPLC Rt=4.3 minutes

[0438] Intermediate 53:

[0439] {3-ethyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methanol

[0440] Prepared from intermediate 43 and methylmagnesium bromide

[0441] HPLC Rt=3.2 minutes

[0442] Intermediates 5442 were prepared from intermediate 44 by methodsanalogous to those described above for the preparation of intermediate46

[0443] Intermediate 54:

[0444]{2-[(benzylthio)methyl]-5-[4-trifluoromethyl)phenyl]-3-furyl}methanol

[0445] Prepared from intermediate 44 and benzyl mercaptan

[0446] HPLC Rt=4.0 minutes

[0447] Intermediate 55:

[0448] {2-(phenoxymethyl)-5-[4-trifluoromethyl)phenyl]-3-furyl}methanol

[0449] Prepared from intermediate 44 and phenol

[0450]¹H NMR (CDCl₃) δ 7.79 (d, 2H), 7.65 (d, 2H), 7.35 (t, 2H), 7.0 (m,3H), 6.83 (s, 1H), 5.12 (s, 2H), 4.65 (d, 2H),

[0451] Intermediate 56:

[0452]{2-[(isopropylthio)methyl]-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol

[0453] Prepared from intermediate 44 and isopropylthiol

[0454]¹H NMR (CDCl₃) δ 7.75 (d, 2H), 7.63 (d, 2H), 6.8 (s, 1H), 7.58 (d,2H), 7.87 (s, 2H), 2.95 (m, 1H), 1.90 (t, 1H), 1.31 (d, 6H)

[0455] Intermediate 57:

[0456]{2-{[methyl(phenyl)amino]methyl}-5-[4-trifluoromethyl)phenyl]-3-furyl}methanol

[0457] Prepared from intermediate 44 and N-methyl aniline

[0458]¹H NMR (CDCl₃) δ 7.74 (d, 2H), 7.65 (d, 2H), 6.34 (m, 3H), 6.0 (d,2H), 5.9 (t, 1H), 5.8 (s, 1H)

[0459] Intermediate 58:

[0460]{2-{[(2-furylmethyl)thio]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol

[0461] Prepared from intermediate 44 and furan-2-methanethiol

[0462] tlc: cyclohexane: ethylacetate (1:1) R_(f)=0.42

[0463] Intermediate 59:

[0464]{2-{[(3,5-dimethylphenyl)thio]methyl}-5-[4-trifluoromethyl)phenyl]-furyl}methanol

[0465] Prepared from intermediate 44 and 3,5-dimethylthiophenol

[0466] tlc: cyclohexane: ethylacetate (1:1) R_(f)=0.52

[0467] Intermediate 60:

[0468]{2-{[(2,4-difluorophenyl)thio]methyl}-5-[4-trifluoromethyl)phenyl]-3-furyl}methanol

[0469] Prepared from intermediate 44 and 2,4-difluorothiophenol

[0470] tlc: cyclohexane:ethyl acetate (1:1) R_(f)=0.49

[0471] Intermediate 61:

[0472]{2-{[(1H-benzimidazol-2-ylmethyl)thio]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol

[0473] Prepared from intermediate 44 and benzimidazole-2-methanethiol

[0474] tlc: dichloromethane:methanol: “880” ammonia (196:3:1) R_(f)=0.14

[0475] Intermediate 62:

[0476]({3-(methoxycarbonyl)-5-[4-(trifluoromethyl)phenyl]-2-furyl}methyl)(triphenyl)phosphoniumbromide

[0477] Methyl 2-bromomethyl-5-[4-(trifluoromethyl)phenyl]-3-furoate(intermediate 44, 0.20 g) was dissolved in toluene (3 ml) treated withtriphenylphosphine (0.159 g) and heated to reflux for 1 hour. Thereaction was allowed to cool and the white precipitate was collected byfiltration, washed with fresh toluene to give the title compound as awhite powder.

[0478] HPLC Rt=4.0 minutes

[0479] Intermediate 63:

[0480]methyl2-[(E)-2-pyridin-4-ylethenyl]-5-[4-(trifluoromethyl)phenyl]-3-furoatehydrochloride

[0481]({3-(Methoxycarbonyl)-5-[4-(trifluoromethyl)phenyl]-2-furyl}methyl)(triphenyl)phosphoniumbromide (intermediate 62, 0.200 g) was suspended in dry tetrahydrofuran(4 ml). Potassium t-butoxide (0.40 g) was added and the bright orangereaction mixture was allowed to stir for 25 minutes at ambienttemperature. 4-Pyridinecarboxaldehyde (0.034 ml) was added and thereaction allowed to stir for 4.5 hours. The solvent was removed byevaporation and the residue partitioned between chloroform and water.The organic layer was dried using a hydrophobic frit, re-concentrated toa small volume under reduced pressure and loaded onto SPE (Si cartridge)eluting with a gradient from 25:1 to 4:1 cyclohexane:ethyl acetate. Theresulting material was acidified with 2M aqueous hydrochloric acid,concentrated under reduced pressure, then triturated with diethyl etherto give the title compound as a yellow powder.

[0482]¹H NMR (MeOD) δ 8.81 (d, 2H), 8.3 (d, 1H), 8.14 (d, 2H), 7.85 (d,2H), 7.75 (d, 1H), 7.52 (s, 1H), 4.0 (s, 3H)

[0483] Intermediate 64:

[0484] methyl2-(2-pyridin-4-ylethyl)-5-[4-(trifluoromethyl)phenyl]-3-furoatehydrochloride

[0485] Methyl2-[(E)-2-pyridin-4-ylethenyl]-5-[4-(trifluoromethyl)phenyl]-3-furoatehydrochloride (intermediate 62, 0.88 g) was dissolved in ethyl alcohol(5 ml) and added to palladium on carbon (wet Degussa type E101 NE/W).The reaction mixture was stirred at ambient temperature under a hydrogenatmosphere for 4 hours. The catalyst was removed by filtration throughHarbolite J2 and the filtrate concentrated to give the title compound aspale yellow sticky solid.

[0486]¹H NMR (MeOD) δ 8.63 (d, 2H), 7.89 (d, 2H), 7.73 (d, 2H), 7.61 (d,2H), 7.09 (s, 1H), 3.73 (s, 3H), 3.5 (t, 2H), 3.35 (t, 2H).

[0487] Intermediate 65:

[0488] {2-(2-pyridinylethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol

[0489] Methyl2-(2-pyridin-4-ylethyl)-5[4-(trifluoromethyl)phenyl]-3-furoatehydrochloride (intermediate 64, 0.69 g) was suspended in drytetrahydrofuran (4 ml), cooled in ice and treated with 1M lithiumaluminium hydride solution in diethyl ether (0.334 ml). The reactionmixture was allowed to warm up to room temperature and stirred for 3hours. 1M Sodium hydroxide solution (2 ml) was added and the reactionstirred for a further 30 minutes. The reaction mixture was concentrated,the residue was partitioned between chloroform and aqueous sodiumhydroxide. The organic layer through hydrophobic frit and finallyconcentrated under reduced pressure to give the title product ascolourless gum.

[0490]¹H NMR (CDCl₃) δ 8.50 (d, 2H), 7.68 (d, 2H), 7.61 (d, 2H), 7.15(d, 2H), 6.71 (s, 1H), 4.34 (s, 2H), 3.06 (s, 4H)

[0491] Intermediates 65-67 were prepared by methodology analogous tothat described above for the preparation of intermediate 64

[0492] Intermediate 66:

[0493]{2-[2-(4-methylphenyl)ethyl]-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol

[0494] prepare from intermediate 62 and 4-methylbenzaldehyde

[0495]¹H NMR (CDCl₃) δ 7.75 (d, 2H), 7.65 (d, 2H), 7.1 (d, 2H), 7.0 (d,2H), 6.7 (s, 1H), 4.18 (s, 2H), 2.96 (m, 4H), 2.30 (s, 3H)

[0496] Intermediate 67:

[0497] {2-isopentyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol

[0498] Prepared from intermediate 62 and 2-methylpropanal

[0499]¹H NMR (CDCl₃) δ 7.71 (d, 2H), 7.62 (d, 2H), 6.78 (s, 1H), 4.55(s, 2H), 2.70 (t, 2H), 1.58 (m, 3H), 0.96 (d, 6H)

[0500] Intermediate 68:

[0501] {2-isobutyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol

[0502] Prepared from intermediate 62 and propanone

[0503]¹H NMR (CDCl₃) δ 7.75 (d, 2H), 7.61 (d, 2H), 6.80 (s, 1H), 4.50(s, 2H), 2.60 (d, 2H), 2.04 (sept, 1H), 0.98 (d, 6H)

[0504] Intermediate 69:

[0505] ethyl[2-methyl-4-(2-thien-2-ylethoxy)phenoxy]acetate

[0506] A solution of ethyl(4-hydroxy-2-methylphenoxy)acetate(intermediate 7, 1.05 g) and 2-(2-thienyl)ethanol (0.64 g) in drytetrahydrofuran was treated with tri-n-butyl phosphine (1.2 g) andazodicarbonyldimorpholide (1.53 g) and the mixture stirred at ambienttemperature for 3 days. The reaction mixture was concentrated and theresidue partitioned between ethyl acetate and water. The organic layerwas collected, dried over sodium sulfate, concentrated and the residuepurified by SPE (Si cartridge) eluting with cyclohexane:ethyl acetate(20:1) to give the title compound as a colourless oil.

[0507]¹H NMR (CDCl₃) δ7.15 (dd, 1H), 6.95 (dd, 1H), 6.9 (dd, 1H), 6.75(s, 1H), 6.65 (s, 2H), 4.55 (s, 2H), 4.25 (q, 2H), 4.1 (t, 2H), 3.25 (t,2H), 2.25 (s, 3H), 1.3 (t, 3H)

[0508] Intermediate 70:

[0509] ethyl{4-[2-(5-bromothien-2-yl)ethoxy]-2-methylphenoxy}acetate

[0510] A solution ofethyl[2-methyl-4-(2-thien-2-ylethoxy)phenoxy]acetate (intermediate 69,0.306 g) in acetic acid (5 ml) was treated with bromine (0.180 g) atambient temperature and the mixture stirred for 15 minutes. The mixturewas poured into water and the resulting suspension extracted withdiethyl ether. The organic layer was separated, dried over sodiumsulfate and concentrated to give the title compound as a colourless oil.

[0511]¹H NMR (CDCl₃) δ 6.9 (d, 2H), 6.75 (d, 1H), 6.65 (d, 3H), 4.55 (s,3H), 4.25 (q, 2H), 4.1 (t, 2H), 3.2 (t, 2H), 2.3 (s, 3H), 1.3 (t, 3H)

[0512] Intermediate 71:

[0513] 5-4-chlorophenyl)-2-methyl-3-furaldehyde

[0514] A mixture 5-(4-chlorophenyl)-3-hydroxymethyl-2-methylfuran(intermediate 32, 0.70 g) in chloroform (50 ml) was treated withmanganese dioxide (5.60 g) and the reaction mixture stirred for 1.20hours. The reaction was filtered through Celite™ and the filtrateevaporated to give the title compound as a colourless solid.

[0515]¹H NMR (CDCl₃) δ 10.0 (s, 1H), 7.6 (d, 2H), 7.4 (d, 2H), 6.9 (s,1H), 2.7 (s, 3H)

[0516] Intermediates 72-74 were prepared by methodology analogous tothat described above for preparation of intermediate 71.

[0517] Intermediate 72:

[0518] 5-[4-trifluoromethyl)phenyl]-2-methyl-34-furaldehyde

[0519] Prepared from intermediate 24

[0520]¹H NMR (CDCl₃) a 10.0 (s, 1H), 7.8 (d, 2H,), 7.7 (d, 2H,), 7.0 (s,1H), 2.7 (s, 3H).

[0521] Intermediate 73:

[0522] 5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furaldehyde

[0523] Prepared from intermediate 30

[0524] HPLC Rt=4.4 minutes

[0525] Intermediate 74:

[0526] 3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-2-carbaldehyde

[0527] Prepared from intermediate 36

[0528] HPLC Rt=2.7 minutes

[0529] Intermediate 75:

[0530] 2-(3-methylthien-2-yl)-1,3-dioxolane

[0531] A mixture of 3-methylthiophene carboxaldehyde (6.8 g), ethyleneglycol (10 ml) and p-toluenesulfonic acid (0.30 g) in toluene (125 ml)was heated at reflux for 18 hours. The reaction mixture was cooled;extracted with 2M aqueous sodium carbonate and then dried with brine andover magnesium sulfate. Analysis of the crude product indicated that thereaction was incomplete so the crude material was re-subjected to theketalisation conditions as outlined above. The crude material isolatedafter reprocessing was distilled under reduced pressure (1 mmHg) to givethe title compound as a yellow oil.

[0532] HPLC Rt=2.8 minutes

[0533] Intermediate 76:

[0534] tributyl[5-(1,3-dioxolan-2-yl)-4-methylthien-2-yl]stannane

[0535] A mixture of 2-(3-methylthien-2-yl)-1,3-dioxolane (intermediate75, 1.5 g) in tetrahydrofuran (50 ml), stirred at −60° C. under anitrogen atmosphere, was treated drop-wise with 1.6M n-butyl lithium inhexanes (6.1 ml). The reaction mixture was stirred at this temperaturefor 1 hour and tributyltin chloride (2.6 ml) was added; stirring wascontinued at −60° C. for 1 hour and then the reaction allowed to warm toambient temperature. After 18 hours the reaction mixture was dilutedwith diethylether and this mixture was extracted with water and theether layer dried with brine and over magnesium sulfate. The productisolated after evaporation of the solvent was further purified by flashcolumn chromatography using cyclohexane:ethyl acetate (50:1) as eluentto give the title compound as a yellow oil.

[0536] HPLC Rt=4.9 minutes

[0537] Intermediate 77:

[0538] 3-methyl-5-(tributylstannyl)thiophene-2-carbaldehyde

[0539] A mixture oftributyl[5-(1,3-dioxolan-2-yl)₄-methylthien-2-yl]stannane (intermediate76, 2.92 g), 1M aqueous hydrochloric acid (3 ml) and tetrahydrofuran (10ml) was stirred at reflux for 30 minutes. The reaction mixture wascooled, extracted thrice with diethylether. The organic solutions werecombined, extracted with saturated sodium bicarbonate and dried withbrine and over magnesium sulfate. The product isolated after evaporationof the solvent was further purified by flash column chromatography usingcyclohexane:ethyl acetate (50:1) as eluent to give the title compound asa yellow oil.

[0540] HPLC Rt=0.8 minutes

[0541] Intermediate 78:

[0542]3-methyl-5-[5-trifluoromethyl)pyridin-2-yl]thiophene-2-carbaldehyde

[0543] A mixture of 2-bromo-4-trifluoromethylpyridine (0.073 g),tetrakis(triphenylphosphine)palladium (0) (0.019 g) and silver oxide(0.074 g) in N,N-dimethylformamide was heated at 100° C. for 5 minutes.A solution of 3-methyl-5-(tributylstannyl)thiophene-2-carbaldehyde(intermediate 77, 0.095 g) in N,N-dimethylformamide (2 ml) was added andthe reaction stirred for 5 minutes at 100° C. The reaction mixture wascooled, N,N-dimethylformamide removed and a solution of the residue indichloromethane filtered through Celite® 545. The solvent was evaporatedand the residue further purified by flash column chromatography usingcyclohexane:ethyl acetate (50:1) as eluent to give the title compound asa yellow oil.

[0544] HPLC Rt=3.6 minutes

[0545] Intermediate 79:

[0546] {3-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]thien-2-yl}methanol

[0547] A mixture of3-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]thiophene-2-carbaldehyde(intermediate 78, 0.144 g) in tetrahydrofuran (10 ml) and water (15 ml)was treated with sodium borohydride (0.03 g). The reaction was stirredat room temperature for 30 minutes, extracted with ethyl acetate and theorganic layer washed with water and dried with brine and over magnesiumsulfate. The title compound was isolated after removal of the desiccantand evaporation of the solvent.

[0548] HPLC Rt=3.4 minutes

[0549] Intermediate 80:

[0550] [3-methyl-5-(tributylstannyl)thien-2-yl]methanol

[0551] Prepared using a method analogous to the preparation ofintermediate 79 using intermediate 77.

[0552] HPLC Rt=4.8 minutes

[0553] Intermediate 81:

[0554]ethyl(2-methyl-4-{[3-methyl-5-(tributylstannyl)thien-2-yl]methoxy}phenoxy)acetate

[0555] The title compound was prepared from intermediates 7 and 80 usinga procedure analogous to that used for the preparation of intermediate69.

[0556] HPLC Rt=5.1 minutes

[0557] Intermediate 82:

[0558] 5-bromo-3-methylthiophene-2-carbaldehyde

[0559] A solution of 3-methyl-thiophene-2-carboxaldehyde (12.0 g) inchloroform (50 ml) was added drop-wise to bromine (5.1 ml) in chloroformover 30 minutes and then heated to 100° C. for 140 minutes. The reactionmixture was diluted with chloroform and washed with 10% aqueous sodiumthiosulfate solution, saturated aqueous bicarbonate solution and water.The organic solution was dried over magnesium sulfate and concentrated.The product isolated after evaporation of the solvent was furtherpurified by vacuum distillation (122° C., 4 mbar) to give the titlecompound as a green oil.

[0560]¹H NMR (CDCl₃) δ 9.9 (s, 1H), 6.95 (s, 1H), 2.55 (s, 3H)

[0561] Intermediate 83:

[0562] (5-bromo-3-methylthien-2-yl)methanol

[0563] A mixture of 1-(5-bromo-3-methylthien-2-yl)ethanone (intermediate82, 5.13 g) in ethanol (50 ml) was treated with sodium borohydride(0.947 g). The reaction was stirred at 0° C. for 60 minutes and warmedto room temp for 30 minutes. 2M Aqueous hydrochloric acid was added andthe reaction mixture was extracted with ethyl acetate twice. The organicsolutions were combined and dried with brine and over magnesium sulfate.The title compound was isolated after removal of the desiccant andevaporation of the solvent.

[0564] HPLC Rt=3.0 minutes

[0565] Intermediate 84:

[0566]ethyl{4-[(5-bromo-3-methylthien-2-yl)methoxy]-2-methylphenoxy}acetate

[0567] The title compound was prepared from intermediates 7 and 83 usinga procedure analogous to that used for the preparation of intermediate69.

[0568] HPLC Rt=4.1 minutes.

[0569] Intermediate 85:

[0570] [5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]acetonitrile

[0571] To a solution of 1M potassium tert-butoxide solution intetrahydrofuran (5.9 ml) in dry ethylene glycol dimethyl ether (80 ml)at −78° C. under nitrogen was added TOSMIC (0.61 g) in ethylene glycoldimethyl ether (10 ml) followed by-5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furaldehyde (intermediate 73,0.770 g) in dry ethylene glycol dimethyl ether (20 ml). The bright redsolution was stirred at −70 to −50° C. for 1.5 hours. Dry methanol (20ml) was then added and the solution was allowed to warm to roomtemperature. After 1 hour the mixture was heated to reflux for 30minutes then allowed to cool back to room temperature. The solution wasconcentrated then partitioned between dichloromethane, water and aceticacid (few drops). The aqueous portion was taken and washed a second timewith dichloromethane. The combined organics were washed with 1M aqueouspotassium carbonate solution then dried (MgSO₄) and concentrated. Thecrude material was purified by SPE (Si): the product was eluted withcyclohexane:chloroform (1:1) and concentrated to form yellow crystals.

[0572]¹H NMR (CDCl₃) δ 7.58 (d, 2H), 7.34 (d, 2H), 6.74 (s, 1H), 3.69(s, 2H)

[0573] Intermediate 86:

[0574] methyl[5-(4-chlorophenyl)-2-trifluoromethyl)-3-furyl]acetate

[0575] A solution of[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]acetonitrile(intermediate 85, 0.171 g) in methanol (20 ml) was cooled to <−40° C.under nitrogen. Hydrogen chloride gas was bubbled through for ˜10minutes until the temperature had stopped rising. This mixture wasstored at −20° C. overnight. The solution was then concentrated andwater (20 ml) was added. This mixture was heated to reflux for 20minutes then allowed to cool to room temperature. Ethyl acetate wasadded; the organic layer was separated and washed with water and brinethen dried (MgSO₄) and concentrated. The crude material was passed downa SPE (Si): the product was eluted using cyclohexane:chloroform (1:1)and concentrated to form a yellow oil.

[0576]¹H NMR (CDCl₃) δ 7.56 (d, 2H), 7.32 (d, 2H), 6.66 (s, 1H), 3.68(s, 3H), 3.59 (s, 2H)

[0577] Intermediate 87:

[0578] 2-[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]ethanol

[0579] 1.5 M Diisobutylaluminium hydride in toluene (0.8 ml) was addedto a solution ofmethyl[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]acetate(intermediate 86, 0.10 g) in tetrahydrofuran (5 ml) at 0° C. undernitrogen. The solution was allowed to stir thus for 2.5 hours then wasquenched with methanol and allowed to warm to room temperature. Silicawas added and the solvent was removed in vacuo. The crude product waspurified using SPE (silica cartridge): the product was eluted usingcyclohexane:ethyl acetate (5:1) and concentrated to form a colourlessoil.

[0580]¹H NMR (CDCl₃)δ 7.62 (d, 2H), 7.38 (d, 2H), 6.66 (s, 1H), 3.88 (q.2H), 2.86 (t, 2H)

[0581] Intermediate 88

[0582]{2-{[isopropyl(methyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3furyl}methanol

[0583] Prepared using intermediate 44 and N-methylisopropylamine. Thiscompound was used directly without collection of analytical data for thepreparation of Example 75.

[0584] Intermediate 89

[0585]{2-{[methyl(2-phenylethyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol

[0586] Prepared using intermediate 44 and N-methylphenethylamine.

[0587]¹H NMR (CDCl₃) δ 7.70 (d, 2H), 7.62 (d, 2H), 7.27 (m, 2H), 7.18(m, 3H), 4.55 (s, 2H), 3.75 (s, 2H), 2.85 (d, t, 2H), 2.75 (d, t, 2H),2.40 (s, 3H)

[0588] Intermediate 90

[0589]{2-{[cyclohexyl(methyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol

[0590] Prepared using intermediate 44 and N-methylcyclohexylamine.

[0591]¹H NMR (CDCl₃) δ, 7.7 (d, 2H), 7.63 (d, 2H), 6.67 (s, 1H), 4.63(s, 2H), 2.43 (m, 1H), 2.24 (s, 3H), 1.85 (m, 4H), 1.64 (d, 1H), 1.2 (m,4H), 1.1 (m, 2H)

[0592] Intermediate 91

[0593]{2-{[(3,5-dimethoxybenzyl)(methyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol

[0594] Prepared using intermediate 44 andN-methyl(3,5-dimethoxy)benzylamine.

[0595]¹H NMR (CDCl₃) δ 7.70 (d, 2H), 7.62 (d, 2H), 6.68 (s, 1H), 6.55(s, 2H), 6.40 (t, 1H), 4.60 (s, 2H), 3.78 (s, 6H), 3.64 (s, 2H), 2.34(s, 3H)

[0596] Intermediate 92

[0597]{2-{[methyl(pyridin-3-ylmethyl)amino]methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol

[0598] Prepared using intermediate 44 andN-methyl(3-pyridyl)methylamine.

[0599]¹H NMR (CDCl₃) δ 8.55 (s, 2H), 7.76, (d, 1H), 7.72 (d, 2H), 7.62(d, 2H), 7.31 (d,d, 1H), 6.69 (s, 1H), 4.61 (s, 2H), 3.79, (s, 2H), 3.67(s, 2H), 2.30 (s, 3H)

[0600] Intermediate 93

[0601] benzyl(4-formyl-2-methylphenoxy)acetate

[0602] Prepared using a method analogous to that used for thepreparation of intermediate 1 using benzyl bromoacetate and3-methyl-4-hydoxybenzaldehyde.

[0603]¹H NMR (CDCl₃) δ 9.98 (s, 1H), 7.71 (s, 1H), 7.64 (1H, d),7.40-7.30 (bs, 5H), 6.75 (d, 1H), 5.24 (s, 2H), 4.78 (s, 2H), 2.34 (3H,s)

[0604] Intermediate 94

[0605] (3-methylthien-2-yl)methanol

[0606] Prepared from commercially available3-methyl-1-thiophenecarboxaldehyde.

[0607]¹H NMR (CDCl₃) δ 7.17 (1H, d), 6.83 (d, 1 Hz), 4.76 (s, 2H), 2.25(3H, s)

[0608] Intermediate 95

[0609] [(3-methylthien-2-yl)methyl](triphenyl)phosphonium bromide

[0610] Prepared using a method analogous to that used for thepreparation of intermediate 14 using intermediate 94.

[0611]¹H NMR (CDCl₃) δ 7.80-7.64 (15H, m), 7.40 (1H, m), 6.83 (d, 1H),5.29 (2H, d), 1.52 (3H, bs)

[0612] Intermediate 96

[0613] E/Z benzyl{2-methyl-4-[2-(3-methylthien-2-yl)ethenyl]phenoxy}acetate

[0614] Sodium hydride (0.204, 60% dispersion in mineral oil) was addedto anhydrous N,N-dimethylformamide (5 ml) followed by[(3-methylthien-2-yl)methyl](triphenyl)phosphonium bromide (intermediate95, 0.2.67 g) after 10 minutes. After a further 10benzyl(4-formyl-2-methylphenoxy)acetate (intermediate 94, 1.42 g) wasadded and the reaction mixture stirred at ambient temperature for 3hours. The reaction mixture was treated with water and then the mixtureextracted with ethyl acetate. The ethyl acetate solution was extractedwith water, 1M aqueous hydrochloric acid, water and finally dried withbrine and over sodium sulfate. The crude product remaining after thistreatment was purified by Biotage® chromatography using a mixture ofpetroleum ether:ethyl acetate (4:1) as eluent to give the titlecompounds as a mixture of isomers.

[0615] HPLC Rt=4.2 and 4.3 minutes.

[0616] Intermediate 97

[0617] {2-methyl-4-[2-3-methylthien-2-yl)ethyl]phenoxy}acetic acid

[0618] Prepared from intermediate 96 using methods analogous to thatused for the preparation of examples 117 and 118.

[0619] HPLC Rt=3.81 minutes

[0620] Intermediate 98

[0621](3-methyloxetan-3-yl)methyl{2-methyl-4-[2-(3-methylthien-2-yl)ethyl]phenoxy}acetate

[0622] A mixture of{2-methyl-4-[2-(3-methylthien-2-yl)ethyl]phenoxy}acetic acid(intermediate 97, 0.615 g) in dichloromethane (10 ml) was treated withWSDCI (0.608 g); DMAP (0.010 g) and 3-methyloxetane-3-methanol (0.433g). The reaction mixture was stirred for 16 hours; extracted with waterand then dried with a hydrophobic frit. The solvent was removed underreduced pressure and the residue purified by Biotage® chromatographyusing a mixture of petroleum ether:ethyl acetate (5:1) as eluent to givethe title compound.

[0623] HPLC Rt=3.8 minutes

[0624] Intermediate 99

[0625]4-methyl-1-({2-methyl-4-[2-(3-methylthien-2-yl)ethyl]phenoxy}methyl)-2,6,7-trioxabicyclo[2.2.2]octane

[0626] A mixture of (3-methyloxetan-3-yl)methyl{2-methyl-4-[2-(3-methylthien-2-yl)ethyl]phenoxy}acetate (intermediate98, 0.673 g) in dichloromethane stirred under nitrofgen in an ice/waterbath was treated with boron trifluoride etherate (0.171 ml). Thereaction mixture was stirred for 4 hours at this temperature thentriethylamine (0.25 ml) added. The solvent was removed and the residuepurified by Biotage® chromatography using a mixture of petroleumether:ethyl acetate (5:1) as eluent to give the title compound.

[0627] HPLC Rt=3.9 minutes

[0628] Intermediate 100

[0629]tributyl[4-methyl-5-(2-{3-methyl-4-[(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)methoxy]phenyl}ethyl)thien-2-yl]stannane

[0630] Prepared from intermediate 99 using methods analogous to thatused for the preparation of intermediate 76.

[0631]¹H NMR (CDCl₃) δ 6.95-6.92 (2H, m), 6.85-6.81 (2H, m), 3.99 (8H,s), 3.00-2.95 (2H, m), 2.84-2.79 (2H, m), 2.25 (s, 3H), 2.19 (s, 3H),1.60-1.51 (6H, m), 1.39-1.29 (6H, m), 1.09-1.04 (6H, m), 0.90 (2H, t)

[0632] Intermediate 101

[0633]2-fluoro-4-[4-methyl-5-(2-{3-methyl-4-[(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)methoxy]phenyl}ethyl)thien-2-yl]benzonitrile

[0634] A mixture oftributyl[4-methyl-5-(2-{3-methyl-4-[(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)methoxy]phenyl}ethyl)thien-2-yl]stannane(intermediate 100, 0.037 g) and 2-fluoro-4-bromobenzonitrile (0.011 g)in tetrahydrofuran (2 ml) was treated with palladiumbis(dibenzylideneacetone) (0.0035 g) and trifuranyl phosphine (0.0013 g)and the resulting mixture stirred at reflux for 3 hours. The solvent wasremoved and the residue purified by Biotage® chromatography using amixture of petroleum ether:ethyl acetate (4:1) as eluent to give thetitle compound.

[0635] HPLC Rt=4.2 minutes

[0636] Intermediate 102

[0637] 4-methyl-2-[4-(trifluoromethyl)phenyl]thiophene

[0638] To a solution of 3-methylthiophene (2.31 ml) in anhydrous THF (75ml) at −78° C. under N₂ was added dropwise n-BuLi (1.6 M in hexanes, 15ml). Thirty minutes after the addition was complete, the reactionmixture was allowed to warm to 0° C. and stirred for a further 30minutes. Zinc chloride (0.5 M in THF, 48 ml) was added drop-wise, aftera further 15 minutes palladium (0) tetrakis(triphenylphosphine) (100 mg)and 4-bromobenzotrifluoride (3.36 ml) were added and the reactionallowed to attain room temperature. The reaction mixture was warmed to40° C. and stirred at this temperature for 3 hours. The reaction mixturewas then cooled to room temperature and the solvents removed in vacuo.The residue was partitioned between and ether and the aqueous extractfurther washed with ether. The combined organic extracts were dried(MgSO₄), filtered and evaporated to yield a brown oil. Purification byBiotage® chromatography eluting with cyclohexane yielded the titlecompound as a white solid.

[0639] HPLC Rt=4.2 minutes

[0640] Intermediate 103

[0641]2-(4-methoxy-3-methylphenyl)-1-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethanone

[0642] To methanesulfonic acid (8 ml) in a flask under N₂ was added P₂O₅(0.56 g), the resulting suspension was heated to 60° C. until a clearsolution formed. The mixture was cooled to room temperature prior toaddition of 4-methoxy-3-methyl-phenylacetic acid (0.3549) and4-methyl-2-[4-(trifluoromethyl)phenyl]thiophene (intermediate 102, 0.4g). The mixture was then heated to 60° C. for 90 minutes. The reactionmixture was cooled to room temperature and then poured into iced water.The suspension was made basic by cautious addition of NaHCO₃ and theproducts extracted into ethyl acetate. The combined organic extractswere dried (MgSO₄), filtered and evaporated to yield a brown oil.Purification by flash column chromatography eluting with 5%EtOAc/cyclohexane yielded the title compound as a brown gum.

[0643] HPLC Rt=4.5 minutes

[0644] Intermediate 104

[0645]2-(4-methoxy-3-methylphenyl)-2-methyl-1-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}propan-1-one

[0646] To a suspension of sodium hydride (60% dispersion in mineral oil,0.105 g) in anhydrous 1,2-dimethoxyethane (1 ml), under nitrogen, wasadded methyl iodide (0.164 ml). A solution of2-(4-methoxy-3-methylphenyl)-1-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethanone(intermediate 103, 0.425 g) in anhydrous 1,2-dimethoxyethane (2 ml) wasthen added drop-wise. After the addition was complete the reactionmixture was stirred at room temperature for 1 hour prior to heating to80° C. for 18 hours. After cooling to room temperature, water was addedand the product extracted into ether. The combined organic extracts weredried (MgSO₄) filtered and evaporated, to yield the title compound as ayellow oil.

[0647] HPLC Rt=4.5 minutes

[0648] Intermediate 105

[0649]2-(4-hydroxy-3-methylphenyl)-2-methyl-1-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}propan-1-one

[0650] To2-(4-methoxy-3-methylphenyl)-2-methyl-1-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}propan-1-one(intermediate 104, 0.35 g) in a pressure vessel was added pyridinehydrochloride (10 g), the vessel was sealed and heated to 150° C. for 72hours. The reaction vessel was then allowed to cool to room temperatureand the solid residue partioned between water and CH₂Cl₂, the aqueousextract was further extracted CH₂Cl₂. The combined organic extracts weredried (Na₂SO₄), filtered and evaporated to yield a brown oil.Purification by flash column chromatography eluting with 1%EtOAc/cyclohexane yielded the title compound as a pale yellow oil.

[0651] HPLC Rt=4.3 minutes

[0652] Intermediate 106

[0653]ethyl[4-(1,1-dimethyl-2-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}-2-oxoethyl)-2-methylphenoxy]acetate

[0654] To a solution of2-(4-hydroxy-3-methylphenyl)-2-methyl-1-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}propan-1-one(intermediate 105, 62.0 mg) in anhydrous acetonitrile (2 ml) was addedcaesium carbonate (106 mg) and ethyl bromoacetate (18 μl) and thereaction stirred at room temperature under nitrogen for 20 hours. Thesolid residue was filtered, and the filtrate was concentrated in vacuoand the residue purified by flash column chromatography, eluting with 1%EtOAc/cyclohexane yielded the title compound as a white solid.

[0655]¹H NMR (CDCl₃) 7.57 (d, 2H), 7.51 (d, 2H), 7.15-7.10 (m, 3H), 6.70(dd, 1H), 4.65 (s, 2H), 4.24 (q, 2H), 2.55 (s, 3H), 2.29 (s, 3H), 1.58(s, 6H), 1.26 (t, 3H).

[0656] Intermediate 107

[0657] ethyl(2-ethylphenoxy)acetate

[0658] A mixture of 2-ethylphenol (244 mg) in acetonitrile (20 ml) wastreated with cesium carbonate (650 mg) and ethyl bromoacetate (0.221 ml)and the mixture stirred at 60° C. for 6 hours and then at ambienttemperature for 17 hours. The reaction mixture was diluted with ethylacetate; the suspension filtered and the title compound isolated byevaporation in vacuo of the filtrate as a colourless oil.

[0659]¹H NMR (CDCl₃) 7.187.11 (m, 2H), 6.93 (t, 1H), 6.71 (d, 1H), 4.63(s, 2H), 4.26 (q, 2H), 2.72 (q, 2H), 1.29 (t, 3H), 1.23 (t, 3H).

[0660] Intermediate 108

[0661] ethyl(2-isopropylphenoxy)acetate

[0662] Prepared using a method analogous to the preparation ofethyl(2-ethylphenoxy)acetate (intermediate 107).

[0663]¹H NMR (CDCl₃) 7.24-7.23 (m, 1H), 7.14-7.10 (m, 1H), 6.96 (t, 1H),6.71 (d, 1H), 4.63 (s, 2H), 4.27 (q, 2H), 3.46-3.39 (m, 1H), 1.25 (t,3H), 1.23 (d, 6H).

[0664] Intermediate 109

[0665] ethyl(2-chlorophenoxy)acetate

[0666] Prepared using a method analogous to the preparation ofethyl(2-ethylphenoxy)acetate (intermediate 107)

[0667]¹H NMR (CDCl₃) 7.39 (d, 1H), 7.20 (t, 1H), 6.95 (t, 1H), 6.85 (d,1H), 4.70 (s, 2H), 4.27 (q, 2H), 1.29 (t, 3H)

[0668] Intermediate 110 ethyl(2-bromophenoxy)acetate

[0669] Prepared using a method analogous to the preparation ofethyl(2-ethylphenoxy)acetate (intermediate 107).

[0670]¹H NMR (CDCl₃) 7.56 (d, 1H), 7.24 (t, 1H), 6.88 (t, 1H), 6.82 (d,1H), 4.70 (s, 2H), 4.27 (q, 2H), 1.29 (t, 3H)

[0671] Intermediate 111

[0672] ethyl[4-(chlorosulfonyl)-2-ethylphenoxy]acetate

[0673] A solution of crude ethyl(2-ethylphenoxy)acetate (intermediate107) in chloroform (6 ml) was stirred with chlorosulfonic acid (1.33 ml)at ambient temperature for 4 hours. The reaction mixture was quenched bythe addition of ice and the organic mixture separated by using ahydrophobic frit. The title compound was isolated by evaporation of thisfiltrate.

[0674]¹H NMR (CDCl₃) 7.87-7.85 (m, 2H), 6.81 (d, 1H), 4.76 (s, 2H), 4.29(q, 2H), 2.72 (q, 2H), 1.31 (t, 3H), 1.28 (t, 3H).

[0675] Intermediates 112-114 were repared using an analogous method tothe preparation of ethyl[4-(chlorosulfonyl)-2-ethylphenoxy]acetate(intermediate 111).

[0676] Intermediate 112

[0677] ethyl[4-(chlorosulfonyl)-2-isopropylphenoxy]acetate

[0678] Prepared using intermediate 108.

[0679]¹H NMR (CDCl₃) 7.88-7.84 (m, 2H), 6.82 (d, 1H), 4.77 (s, 2H), 4.29(q, 2H), 3.47-3.40 (m, 1H), 1.31 (t, 3H), 1.29 (d, 6H).

[0680] Intermediate 113

[0681] ethyl[4-(chlorosulfonyl)-2-chlorophenoxy]acetate

[0682] Prepared using intermediate 109.

[0683]¹H NMR (CDCl₃) 8.09 (d, 1H), 7.91 (dd, 1H), 6.94 (d, 1H), 4.84 (s,2H), 4.30 (q, 2H), 1.32 (t, 3H).

[0684] Intermediate 114

[0685] ethyl[4-(chlorosulfonyl)-2-bromophenoxy]acetate

[0686] Prepared using intermediate 110.

[0687]¹H NMR (CDCl₃) 8.25 (d, 1H), 7.95 (dd, 1H), 6.90 (d, 1H), 4.83 (s,2H), 4.30 (q, 2H), 1.32 (t, 3H).

[0688] Intermediate 115

[0689] triisopropyl[(3-methylthien-2-yl)methoxy]silane

[0690] A solution of (3-methylthien-2-yl)methanol (3.20 g) intetrahydrofuran (10 ml) was added to a mixture of sodium hydride (60%dispersion in mineral oil, 1.05 g) in tetrahydrofuran (40 ml). After theevolution of hydrogen had subsided triisopropylsilyl chloride (5.2 ml)was added. The reaction mixture was stirred for 2 hours then dilutedwith ethyl acetate. The mixture was extracted with water, 2M aqueoussodium hydroxide, water and dried with brine and over sodium sulfate.The crude product was purified by Biotage chromatography® using 100:1petroleum ether:ethyl acetate as eluent to give the title compound as acolorless oil.

[0691] HPLC Rt=4.5 minutes

[0692] Intermediate 116

[0693]triisopropyl{[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thien-2-yl]methoxy}silane

[0694] A mixture of triisopropyl[(3-methylthien-2-yl)methoxy]silane(intermediate 115, 1.42 g) in tetrahydrofuran (20 ml), stirred at −78°C. under nitrogen, was treated with 1.6M butyllithium in hexanes (3.9ml). The reaction temperature was slowly allowed to rise to 0° C. over 2hours and then re-cooled to −78° C.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.28 ml) was addedand the reaction stirred at this temperature for 4 hours and then warmedto 0° C. The reaction was added to a mixture of saturated ammoniumchloride and ice. The aqueous mixture was extracted with diethyl etherand the organic solution dried with brine and over sodium sulfate.Evaporation of the solvent afforded the title compound as a white solid

[0695] HPLC Rt=4.7 minutes

[0696] Intermediate 117

[0697]triisopropyl({3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methoxy)silane

[0698] A mixture oftriisopropyl{[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thien-2-yl]methoxy}silane(intermediate 116, 0.40 g) in 1,2-dimethoxyethane (12 ml) and water (6ml) was treated with 4-bromo-trifluoromethoxybenzene (0.26 g), sodiumcarbonate (0.26 g) and tetrakis(triphenylphosphine)palladium (0) (0.120g). The reaction mixture was stirred at reflux for 2 hours and thenpartitioned between water and ethyl acetate. The aqueous layer wasseparated and extracted with further ethyl acetate and then the organicsolutions combined and dried over magnesium sulfate. The crude productwas purified by Si SPE using dichloromethane as eluent to give the titlecompound as a yellow gum.

[0699] HPLC Rt=5.0 minutes

[0700] Intermediate 118

[0701] {3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methanol

[0702] A mixture oftriisopropyl({3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methoxy)silane(intermediate 117, 0.97 g) in tetrahydrofuran (30 ml) was treated withtetraethylammonium fluoride (0.392 g) and the reaction mixture stirredat ambient temperature for 1 hour. The solvent was evaporated and theresidue purified by flash column chromatography using cyclohexane:ethylacetate (2:1) as eluent to give the title compound.

[0703] HPLC Rt=3.7 minutes

[0704] Intermediate 119

[0705]({5-[2,5-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)(triisopropyl)silane

[0706] The title compound was prepared using a method analogous to thatused for the preparation oftriisopropyl({3-methyl-5[4-(trifluoromethoxy)phenyl]thien-2-yl}methoxy)silane(intermediate 117) using 2,5-difluoro-4-(trifluoromethylbromo)benzene.

[0707] HPLC Rt=5.0 minutes

[0708] Intermediate 120

[0709]{5-[2,5-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methanol

[0710] The title compound was prepared using a method analogous to thatused for the preparation of{3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methanol(intermediate 118) using({5-[2,5-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)(triisopropyl)silane(intermediate 119).

[0711] HPLC Rt=3.7 minutes

[0712] Intermediate 121

[0713]({5-[2,3-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)(triisopropyl)silane

[0714] The title compound was prepared using a method analogous to thatused for the preparation oftriisopropyl({3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methoxy)silane(intermediate 117) using 2,3-difluoro-4-(trifluoromethylbromo)benzene.

[0715] HPLC Rt=5.0 minutes

[0716] Intermediate 122

[0717]{5-[2,3-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methanol

[0718] The title compound was prepared using a method analogous to thatused for the preparation of{3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methanol(intermediate 118) using({542,3-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)(triisopropyl)silane(intermediate 121).

[0719] HPLC Rt=3.7 minutes

[0720] Intermediate 123

[0721]({5-[2-fluoro-4-trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)(triisopropyl)silane

[0722] The title compound was prepared using a method analogous to thatused for the preparation oftriisopropyl({3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methoxy)silane(intermediate 117) using 3-fluoro-4-(trifluoromethylbromo)benzene.

[0723] HPLC Rt=5.0 minutes

[0724] Intermediate 124

[0725]{5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methanol

[0726] The title compound was prepared using a method analogous to thatused for the preparation of{{3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methanol(intermediate 118) using({5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)(triisopropyl)silane(intermediate 123).

[0727] HPLC Rt=3.7 minutes

[0728] Intermediate 125

[0729] 4-[4-(trifluoromethyl)phenyl]thiophene-3-carbaldehyde

[0730] The title compound was prepared using a method analogous to thatused for the preparation of4-[4-(trifluoromethyl)phenyl]thiophene-2-carbaldehyde

[0731] using 2-bromothiophene-4-carboxaldehyde (Foumari, P. et al.,Bull. Soc. Chim. Fr., 1967, 41154120) and 4-trifluoromethylbenzeneboronic acid.

[0732] HPLC Rt=4.1 minutes

[0733] Intermediate 126

[0734] 1-(5-[4-(trifluoromethyl)phenyl]thien-3-yl}ethanol

[0735] A solution of methyl magnesium bromide (13.9 ml, 1.4M solution inTHF/toluene) diluted with THF (30 ml) at 0° C. was treated with asolution of 4-[4-(trifluoromethyl)phenyl]thiophene-3-carbaldehyde(intermediate 125, 1.0 g) in THF (30 ml). The reaction mixture wasallowed to ambient temperature, stirred for 3 hours and aqueous ammoniumchloride added. The reaction mixture was partitioned with ethyl acetateand the organic layer separated; the aqueous layer was further extractedwith ethyl acetate; the organic layers combines and extracted with waterand dried with brine and over sodium sulfate. The crude product waspurified by SPE (Si cartridge) using cyclohexane:ethyl acetate mixturesas eluents to give the title compound as a cream solid.

[0736] HPLC Rt=3.5 minutes

[0737] Intermediate 127

[0738] phenyl{5-[4-(trifluoromethyl)phenyl]thien-3-yl}methanol

[0739] The title compound was prepared using a method analogous to thatused for the preparation of1-5-[4-(trifluoromethyl)phenyl]thien-3-yl}ethanol (intermediate 126)using 4-[4-(trifluoromethyl)phenyl]thiophene-3-carbaldehyde(intermediate 125) and phenyl magnesium bromide.

[0740] HPLC Rt=3.8 minutes

[0741] Intermediate 128

[0742] 5-[4-(trifluoromethyl)phenyl]thiophene-2-carbaldehyde

[0743] The title compound was prepared using a method analogous to thatused for the preparation of4-[4-(trifluoromethyl)phenyl]thiophene-2-carbaldehyde

[0744] (intermediate 37) using 2-bromothiophene-5-carboxaldehyde and4-trifluoromethylbenzene boronic acid.

[0745] HPLC Rt=3.6 minutes

[0746] Intermediate 129

[0747] 1-{5-[4-trifluoromethyl)phenyl]thien-2-yl}ethanol

[0748] The title compound was prepared using a method analogous to thatused for the preparation of1-{5-[4-(trifluoromethyl)phenyl]thien-3-yl}ethanol (intermediate 126)using 5-[4-(trifluoromethyl)phenyl]thiophene-2-carbaldehyde(intermediate 128) and methyl magnesium bromide.

[0749] HPLC Rt=3.6 minutes

[0750] Intermediate 130

[0751] 1-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethanol

[0752] The title compound was prepared using a method analogous to thatused for the preparation of1-{5-[4-(trifluoromethyl)phenyl]thien-3-yl}ethanol (intermediate 126)using 3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-2-carbaldehyde(intermediate 74) and methyl magnesium bromide.

[0753] HPLC Rt=3.8 minutes

[0754] Intermediate 130

[0755] 3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylic acid

[0756] The title compound was prepared using3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-2-carbaldehyde(intermediate 74) by a method analogous to the preparation of4-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylic acid (intermediate38).

[0757] HPLC Rt=4.0 minutes

[0758] Intermediate 131

[0759] methyl3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate

[0760] A mixture of3-methyl-5[4-(trifluoromethyl)phenyl]thiophene-2-carboxylic acid(intermediate 130, 8.1 g) in methanol (300 ml) was heated at 30° C. andhydrogen chloride gas bubbled through the mixture. The reaction mixturewas then stirred at reflux for 21 hours; cooled and treated with furtherhydrogen chloride gas. The reaction mixture was stirred at reflux for afurther 6 hours, cooled and concentrated. The resulting precipitate wasfiltered and washed with cyclohexane to give the title compound as asolid.

[0761]¹H NMR (CD₃OD) 7.85 (d, 2H), 7.70 (d, 2H), 7.41 (s, 1H), 3.86 (s,3H), 2.55 (s, 3H).

[0762] Intermediate 132

[0763] methyl3-(bromomethyl)-5-[4-trifluoromethyl)phenyl]thiophene-2-carboxylate

[0764] The title compound was prepared using a method analogous to thatused for the preparation of ethyl3-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate(intermediate 43) using methyl3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate(intermediate 131).

[0765]¹H NMR (CDCl₃) 7.73 (d, 2H), 7.68 (d, 2H), 7.45 (s, 1H), 4.92 (s,2H), 3.94 (s, 3H).

[0766] Intermediates 133-138 were prepared using intermediate 133 bymethods analogous to those described above for the preparation ofintermediate 46

[0767] Intermediate 133

[0768]{5-[4-(trifluoromethyl)phenyl]-3-[(isopropylthio)methyl]thien-2-yl}methanol

[0769] The title compound was prepared using methyl3-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate(intermediate 132) and isopropylthiol.

[0770]¹H NMR (CDCl₃) 7.66 (d, 2H), 7.61 (d, 2H), 7.26 (s, 1H), 4.80 (s,2H), 3.79 (s, 2H), 2.92 (m, 1H), 1.30 (d,6H).=

[0771] Intermediate 134

[0772]{5-[4-(trifluoromethyl)phenyl]-3-[(2,3,6-trimethylphenoxy)methyl]thien-2-yl}methanol

[0773] The title compound was prepared using methyl3-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate(intermediate 132) and 2,5,6-trimethylphenol.

[0774]¹H NMR (CDCl₃) 7.70 (d, 2H), 7.64 (d, 2H), 7.38 (s, 1H), 6.96 (d,1H), 6.89 (d, 1H), 4.83 (s, 2H), 4.79 (s, 2H), 2.27 (s, 3H), 2.25 (s,3H), 2.21 (s, 3H).

[0775] Intermediate 135

[0776]{3-{[(2-isopropyl-6-methylpyrimidin-4-yl)oxy]methyl}-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methanol

[0777] The title compound was prepared using methyl3-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate(intermediate 132) and 2-isopropyl-6-methyl-4-pyrimidinol.

[0778]¹H NMR (CDCl₃) 7.66 (d, 2H), 7.62 (d, 2H), 7.40 (s, 1H), 6.45 (s,1H), 5.49 (s, 2H), 4.53 (s, 2H), 3.09 (m, 1H), 2.47 (s, 3H), 1.32 (d,6H).

[0779] Intermediate 136

[0780]{2-[(quinolin-2-ylthio)methyl]-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol

[0781] The title compound was prepared using methyl2-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]-3-furoate (intermediate44) and 2-quinolinethiol.

[0782] HPLC Rt=4.0 minutes

[0783] Intermediate 137

[0784]{2-{[(3-phenyl-1H-1,2,4-triazol-5-yl)thio]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol

[0785] The title compound was prepared using methyl2-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]-3-furoate (intermediate44) and 3-phenyl-1,2,4-triazole-5-thiol.

[0786] HPLC Rt=3.6 minutes

[0787] Intermediate 138

[0788]{2-{[4-(4-methoxyphenyl)piperazin-1-yl]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol

[0789] The title compound was prepared using methyl2-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]-3-furoate (intermediate44) and 1-(4-methoxyphenyl)piperazine.

[0790] HPLC Rt=3.1 minutes

EXAMPLES Example 1

[0791]ethyl{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate

[0792] A solution of {5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol(0.15 g) in tetrahydrofuran (15 ml) stirred at 0° C. was treated withtributylphosphine (0.2 ml), as solution ofethyl(4-mercapto-2-methylphenoxy)acetate (0.150 g) in tetrahydrofuran (2ml) and finally azodicarbonyldimorpholide (0.204 g). The reaction wasallowed to warm to ambient temperature and stirred for 18 hours. Thesolvent was evaporated and the residue subjected to an aqueous work upusing ethyl acetate and water. The organic phase was dried overmagnesium sulfate. The product isolated after evaporation of the solventwas further purified by flash column chromatography using acyclohexane:ethyl acetate (5:1) as eluent to give the title compound.

Example 2

[0793]2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[0794] A mixture ofethyl{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate(example 1, 0.050 g) in tetrahydrofuran (4 ml) and 2M aqueous sodiumhydroxide (4 ml) was stirred at 60° C. for 2 hours. The solvent wasevaporated and the residue partitioned between ether and water; theaqueous layer was acidified using 10% w/v aqueous citric acid and thethen extracted thrice with ethyl acetate. The combined ethyl acetatesolutions were dried over magnesium sulfate and evaporated to give thetitle compound.

[0795] m/z (M−H)⁻=420

[0796] HPLC Rt=4.6 minutes

[0797] The following compounds were prepared by analogous methodology tothat described for the preparation of examples 1 and 2.

Example 3

[0798]ethyl{2-methyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate

[0799] Prepared from intermediates 4 and 24

Example 4

[0800]{2-methyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[0801] Prepared by hydrolysis of example 3

[0802] m/z (M−H)⁻=434

[0803] HPLC Rt=5.1 minutes

Example 5

[0804]ethyl{2-methyl-4-[({3-methyl-5-[4-(trifluoromethyl)phenyl]-2-furyl}methyl)thio]phenoxy}acetate

[0805] Prepared from intermediates 4 and 25

Example 6

[0806]{2-methyl-4-[({3-methyl-5-[4-(trifluoromethyl)phenyl]-2-furyl}methyl)thio]phenoxy}aceticacid

[0807] Prepared by hydrolysis of example 5

[0808] m/z (M−H)⁻=436

[0809] HPLC Rt=4.8 minutes

Example 7

[0810]ethyl{2-methyl-4[({5-[4-(trifluoromethyl)phenyl]-2-furyl}methyl)thio]phenoxy}acetate

[0811] Prepared from intermediates 4 and 26

Example 8

[0812]{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-2-furyl}methyl)thio]phenoxy}aceticacid

Example 9

[0813]ethyl{2-methyl-4[({5-[4-(trifluoromethyl)phenyl]thien-3-yl}methyl)thio]phenoxy}acetate

[0814] Prepared from intermediates 4 and 29

Example 10

[0815]2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-thienyl}methyl)thio]phenoxy}aceticacid

[0816] Prepared by hydrolysis of example 9

[0817] HPLC Rt=4.3 minutes

[0818] m/z (M−H)⁻=448

Example 11

[0819]ethyl{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}acetate

[0820] Prepared from intermediates 4 and 28

Example 12

[0821]2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-2-thienyl}methyl)thio]phenoxy}aceticacid

[0822] Prepared by hydrolysis of example 11

[0823] HPLC Rt=5.2 minutes

[0824] m/z (M−H)⁻=437

Example 13

[0825]ethyl{2-methyl-4-[({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}acetate

[0826] Prepared from intermediates 4 and 24

Example 14

[0827]{2-methyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[0828] Prepared by hydrolysis of example 13

[0829] HPLC Rt=5.1 minutes

[0830] m/z (M−H)⁻=435

Example 15

[0831]Ethyl{2-methyl-4[({3-methyl-4-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}acetate

[0832] Prepared from intermediates 4 and 36

Example 16

[0833]{2-methyl-4-[({3-methyl-4-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid

[0834] Prepared by hydrolysis of example 15

[0835] HPLC Rt=4.0 minutes

[0836] m/z (M−H)⁻=451

Example 17

[0837]ethyl[4-({[5-[4-(trifluoromethyl)phenyl]-2-methyl-3-furyl]methyl}thio)-2-methylphenoxy]acetate

[0838] Prepared from intermediates 4 and 42

Example 18

[0839]{2-methyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]thien-3-yl}methyl)thio]phenoxy}aceticacid

[0840] Prepared by hydrolysis of example 17

[0841] HPLC Rt=4.6 minutes

[0842] m/z (M−H)⁻=451

Example 19

[0843]ethyl[4-({[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]methyl}thio)-2-methylphenoxy]acetate

[0844] Prepared from intermediates 4 and 30

Example 20

[0845][4-({[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]methyl}thio)-2-methylphenoxy]aceticacid

[0846] Prepared by hydrolysis of example 19

[0847] m/e (M−H)⁻=455/457

[0848] HPLC Rt=4.5 minutes

Example 21

[0849]ethyl{2-methyl-4[({2-(trifluoromethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate

[0850] Prepared from intermediates 4 and 31

Example 22

[0851]2-methyl-4-[({2-(trifluoromethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[0852] Prepared by hydrolysis of example 21

[0853] m/z (M−H)⁻=489

[0854] HPLC Rt=4.9 minutes

Example 23

[0855]ethyl{2-methyl-4-[({2-methyl)-5-[4-chlorophenyl]-3-furyl}methyl)thio]phenoxy}acetate

[0856] Prepared from intermediates 4 and 32

Example 24

[0857][4-({[5-(4-chlorophenyl)-2-methyl-3-furyl]methyl}thio)-2-methylphenoxy]aceticacid

[0858] Prepared by hydrolysis of example 23

[0859] m/z (M−H)⁻=402

[0860] HPLC Rt=5.2 minutes

Example 25

[0861]ethyl[2-methyl-4-({3-methyl-5-[5-trifluoromethyl)pyridin-2-yl]thien-2-yl}methoxy)phenoxy]acetate

[0862] Prepared from intermediates 7 and 79

Example 26

[0863][2-methyl-4-({3-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]thien-2-yl}methoxy)phenoxy]aceticacid

[0864] Prepared by hydrolysis of example 25

[0865] m/z (M−H)⁻=436

[0866] HPLC Rt=4.2 minutes

Example 27

[0867]ethyl(4-{[5-(4-chlorophenyl)-2-methyl-3-furyl]methoxy}-2-methylphenoxy)acetate

[0868] Prepared from intermediates 7 and 32

Example 28

[0869](4-{[5-(4-chlorophenyl)-2-methyl-3-furyl]methoxy}-2-methylphenoxy)aceticacid

[0870] Prepared by hydrolysis of example 27

[0871] m/z (M−H)⁻=385

[0872] HPLC Rt=4.5 minutes

Example 29

[0873]ethyl[2-methyl-4-({2-trifluoromethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenoxy]acetate

[0874] Prepared from intermediates 7 and 31

Example 30

[0875][2-methyl-4-({2-(trifluoromethyl)-5-[4-4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenoxy]aceticacid

[0876] Prepared by hydrolysis of example 29

[0877] m/z (M−H)⁻=473

[0878] HPLC Rt=4.0 minutes

Example 31

[0879]ethyl[2-methyl-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenoxy]acetate

[0880] Prepared from intermediates 7 and 24

Example 32

[0881][2-methyl-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenoxy]aceticacid

[0882] Prepared by hydrolysis of example 31

[0883] m/z (M−H)⁻=419

[0884] HPLC Rt=4.0 minutes

Example 33

[0885]ethyl[2-methyl-4-({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)phenoxy]acetate

[0886] Prepared from intermediates 7 and 36

Example 34

[0887][2-methyl-4-({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)phenoxy]aceticacid

[0888] Prepared by hydrolysis of example 33

[0889] m/z (M−H)⁻=435

[0890] HPLC Rt=4.2 minutes

Example 35

[0891]ethyl[2-methyl-4-({3-methyl-5-[4-(trifluoromethyl)phenyl]-2-furyl}methoxy)phenoxy]acetate

[0892] Prepared from intermediates 7 and 25

Example 36

[0893][2-methyl-4-({3-methyl-5-[4-(trifluoromethyl)phenyl]-2-furyl}methoxy)phenoxy]aceticacid

[0894] Prepared by hydrolysis of example 35

[0895] m/z (M−H)⁻=419

[0896] HPLC Rt=3.9 minutes

Example 37

[0897]ethyl3-(4-{[5-(4-chlorophenyl)-2-trifluoromethyl)-3-furyl]methoxy}phenyl)propanoate

[0898] Prepared from intermediates 7 and 30

Example 38

[0899](4-{[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]methoxy}-2-methylphenoxy)aceticacid

[0900] Prepared by hydrolysis of example 37

[0901] m/z (M−H)⁻=439

[0902] HPLC Rt=4.4 minutes

Example 39

[0903]ethyl[2-methyl-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]thien-3-yl}methoxy)phenoxy]acetate

[0904] Prepared from intermediates 7 and 42

Example 40

[0905]{2-methyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]thien-3-yl}methoxy)-2-methylphenoxy}aceticacid

[0906] Prepared by hydrolysis of example 39

[0907] m/z (M−H)⁻=436

[0908] HPLC Rt=4.3 minutes

Example 41

[0909] ethyl2-(4-{[5-(4-chlorophenyl)-2-methyl-3-furyl]methoxy}-2-methylphenoxy)-2-methylpropanoate

[0910] Prepared from intermediates 10 and 32

Example 42

[0911]2-(4-{[5-(4-chlorophenyl)-2-methyl-3-furyl]methoxy}-2-methylphenoxy)-2-methylpropanoicacid

[0912] Prepared by hydrolysis of example 41

[0913] m/z (M−H)⁻=413

[0914] HPLC Rt=4.3 minutes

Example 43

[0915]ethyl2-methyl-2-[2-methyl-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenoxy]propanoate

[0916] Prepared from intermediates 10 and 24

Example 44

[0917]2-methyl-2-[2-methyl-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenoxy]propanoicacid

[0918] Prepared by hydrolysis of example 43

[0919] m/z (M−H)⁻=447

[0920] HPLC Rt=4.3 minutes

Example 45

[0921] ethyl2-methyl-2-[2-methyl-4-({2-trifluoromethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenoxy]propanoate

[0922] Prepared from intermediates 10 and 31

Example 46

[0923]2-methyl-2-[2-methyl-4-({2-trifluoromethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenoxy]propanoicacid

[0924] Prepared by hydrolysis of example 45

[0925] m/z (M−H)⁻=501

[0926] HPLC Rt=4.4 minutes

Example 47

[0927] ethyl2-methyl-2-[2-methyl-4-({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)phenoxy]propanoate

[0928] Prepared from intermediates 10 and 36

Example 48

[0929]2-methyl-2-[2-methyl-4-({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)phenoxy]propanoicacid

[0930] Prepared by hydrolysis of example 47

[0931] m/z (M−H)⁻=463

[0932] HPLC Rt=4.4 minutes

Example 49

[0933] ethyl2-(4-{[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]methoxy}-2-methylphenoxy)-2-methylpropanoate

[0934] Prepared from intermediates 10 and 30

Example 50

[0935]2-(4-{[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]methoxy}-2-methylphenoxy)-2-methylpropanoicacid

[0936] Prepared by hydrolysis of example 49

[0937] m/z (M−H)⁻=467

[0938] HPLC Rt=4.4 minutes

Example 51

[0939] ethyl2-methyl-2-[2-methyl-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]thien-3-yl}methoxy)phenoxy]propanoate

[0940] Prepared from intermediates 10 and 42

Example 52

[0941]2-methyl-2-[2-methyl-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]thien-3-yl}methoxy)phenoxy]propanoicacid

[0942] Prepared by hydrolysis of example 51

[0943] m/z (M−H)⁻=463

[0944] HPLC Rt=4.4 minutes

Example 53

[0945] ethyl3-[4-({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)phenyl]propanoate

[0946] Prepared from commercially available ethyl3-(4-hydroxyphenyl)propanoate and intermediate 36.

Example 54

[0947]3-[4-({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)phenyl]propanoicacid

[0948] Prepared by hydrolysis of example 53

[0949] m/z (M−H)⁻=419

[0950] HPLC Rt=4.1 minutes

Example 55

[0951] ethyl3-(4-{[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]methoxy}phenyl)propanoate

[0952] Prepared from commercially available ethyl3-(4-hydroxyphenyl)propanoate and intermediate 30

Example 56

[0953]3-(4-{[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]methoxy}phenyl)propanoicacid

[0954] Prepared by hydrolysis of example 55

[0955] m/z (M−H)⁻=423

[0956] HPLC Rt=4.2 minutes

Example 57

[0957] ethyl3-(4-{[5-4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]methoxy}-2-methylphenyl)propanoate

[0958] Prepared from intermediates 12 and 30

Example 58

[0959]3-(4-{[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]methoxy}-2-methylphenyl)propanoicacid

[0960] Prepared by hydrolysis example 57

[0961] m/z (M−H)⁻=437

[0962] HPLC Rt=4.3 minutes

Example 59

[0963] ethyl3-[2-methyl-4-({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)phenyl]propanoate

[0964] Prepared from intermediates 12 and 36

Example 60

[0965]3-[2-methyl-4-({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)phenyl]propanoicacid

[0966] Prepared by hydrolysis of example 59

[0967] m/z (M−H)⁻=433

[0968] HPLC Rt=4.3 minutes

Example 61

[0969]ethyl(4-{2-[5-(4-chlorophenyl)-2-trifluoromethyl)-3-furyl]ethoxy}-2-methylphenoxy)acetate

[0970] Prepared from intermediates 7 and 87

Example 62

[0971](4-{2-[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]ethoxy-2-methylphenoxy)aceticacid

[0972] Prepared by hydrolysis of example 61

[0973] m/z (M−H)⁻=453

[0974] HPLC Rt=4.3 minutes

Example 63

[0975]ethyl{2-methyl-4-[({2-(2-pyridin-4-ylethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate

[0976]{2-(2-Pyridin-4-ylethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol(intermediate 65, 0.59 g) was dissolved in dry dichloromethane (4 ml),cooled in ice/water bath and treated with thionyl chloride (0.124 ml).The reaction was allowed to warm up to room temperature, stirred for 2hours and then concentrated under reduced pressure. The residue was thendissolved in acetonitrile (4 ml) followed by sequential addition ofpotassium carbonate (0.47 g) andethyl(4-mercapto-2-methylphenoxy)acetate (intermediate 4, 0.46 g) andallowed to stir overnight at room temperature. The reaction wasconcentrated to dryness, partitioned between chloroform/water. Theorganic layer was dried through a hydrophobic frit, concentrated underreduced pressure and purified using SPE (Si cartridge) usingdichloromethane:methanol: “880” ammonia (196:3:1) as eluent to give thetitle compound as a pale brown gum.

[0977]¹H NMR (CDCl3) δ 8.50 (d, 2H), 7.62 (2×d, 4H), 7.18 (d, 1H), 7.13(m, 2H), 7.09 (d, 1H), 6.62 (s, 1H), 6.59 (d, 1H), 4.61 (s, 2H), 4.24(q, 2H), 3.64 (s, 2H), 2.85 (t, 2H), 2.74 (t, 2H), 2.22 (s, 3H), 1.28(t, 3H)

Example 64

[0978]{2-methyl-4-[({2-(2-pyridin-4-ylethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid hydrochloride

[0979] Prepared by hydrolysis of example 63

[0980] m/z (M−H)⁻=525

[0981] HPLC Rt=3.8 minutes

[0982] The following compounds were prepared in an analogous manner tothat described for the preparation of example 61.

Example 65

[0983]ethyl{4-[({2-[(isopropylthio)methyl]-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}acetate

[0984] Prepared from intermediates 4 and 56

Example 66

[0985]{4-[({2-[(isopropylthio)methyl]-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid

[0986] Prepared by hydrolysis of example 65

[0987] m/z (M−H)⁻=509

[0988] HPLC Rt=4.5 minutes

Example 67

[0989]ethyl{4-[({2-[(1H-benzimidazol-2-ylthio)methyl]-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}acetate

[0990] Prepared from intermediates 4 and 61

Example 68

[0991]{4-[({2-{[(1H-benzimidazol-2-ylmethyl)thio]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid

[0992] Prepared by hydrolysis of example 67

[0993] m/z (M−H)⁻=597

[0994] HPLC Rt=3.9 minutes

Example 69

[0995]ethyl{4-[({2-{[(3,5-dimethylphenyl)thio]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy]acetate

[0996] Prepared from intermediates 4 and 59

Example 70

[0997]{4-[({2-{[(3,5-dimethylphenyl)thio]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid

[0998] Prepared by hydrolysis of example 69

[0999] m/z (M−H)⁻=571

[1000] HPLC Rt=4.8 minutes

Example 71

[1001]ethyl{4-[({2-{[(2,4-difluorophenyl)thio]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}acetate

[1002] Prepared from intermediates 4 and 60

Example 72

[1003]{4-[({2-{[(2,4-difluorophenyl)thio]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid

[1004] Prepared by hydrolysis of example 71

[1005] m/z (M−H)⁻=579

[1006] HPLC Rt=4.6 minutes

Example 73

[1007]ethyl{4-[({2-{[(2-furylmethyl)thio]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}acetate

[1008] Prepared from intermediates 4 and 58

Example 74

[1009](4-[({2-[(2-furylmethyl)thio]methyl}-5-[4-(trifluoromethyl)phenyl]-3furyl}methyl)thio]-2-methylphenoxy]acetic acid

[1010] Prepared by hydrolysis of example 73

[1011] m/z (M−H)⁻=547

[1012] HPLC Rt=4.5 minutes

Example 75

[1013]ethyl{4-[({2-[(benzylthio)methyl]-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}acetate

[1014] Prepared from intermediates 4 and 54

Example 76

[1015]{4-[({3-[(benzylthio)methyl]-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]-2-methylphenoxy}aceticacid

[1016] Prepared by hydrolysis of example 75

[1017] m/z (M−H)⁻=557

[1018] HPLC Rt=4.6 minutes

Example 77

[1019]ethyl{4-[({2-{[isopropyl(methyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}acetate

[1020] Prepared from intermediates 4 and intermediate 88.

Example 78

[1021] {4-[({2-{[isopropyl(methyl)amino]methyl}-5-[4(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid

[1022] Prepared by hydrolysis of example 77

[1023] m/z (M−H)⁻=506

[1024] HPLC Rt=3.2 minutes

Example 79

[1025]ethyl{2-methyl-4-[({2-(phenoxymethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate

[1026] Prepared from intermediates 4 and 55

Example 80

[1027]{2-methyl-4-[({2-(phenoxymethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[1028] Prepared by hydrolysis of example 79

[1029] m/z (M−H)⁻=527

[1030] HPLC Rt=4.5 minutes

Example 81

[1031]ethyl{2-methyl-4-[({2-{[methyl(phenyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate

[1032] Prepared from intermediates 4 and 57

Example 82

[1033] {2-methyl4-[({2-{[methyl(phenyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[1034] Prepared by hydrolysis of example 81

[1035] m/z (M−H)⁻=540

[1036] HPLC Rt=4.7 minutes

Example 83

[1037]ethyl{4-[({2-isobutyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}acetate

[1038] Prepared from intermediates 4 and 68

Example 84

[1039]{4-[({2-isobutyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid

[1040] Prepared by hydrolysis of example 83

[1041] m/z (M−H)⁻=477

[1042] HPLC Rt=4.7 minutes

Example 85

[1043]ethyl{2-methyl-4-[({2-[2-4-methylphenyl)ethyl]-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate

[1044] Prepared from intermediates 4 and 66

Example 86

[1045]{2-methyl-4-[({2-[2-(4-methylphenyl)ethyl]-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[1046] Prepared by hydrolysis of example 85

[1047] m/z (M−H)⁻=539

[1048] HPLC Rt=4.8 minutes

Example 87

[1049]ethyl{4-[({2-isopentyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}acetate

[1050] Prepared from intermediates 4 and 67

Example 88

[1051]{4-[({2-isopentyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid

[1052] Prepared by hydrolysis of example 87

[1053] m/z (M−H)⁻=491

[1054] HPLC Rt=4.8 minutes

Example 89

[1055]ethyl{2-methyl-4-[({2-{[methyl(2-phenylethyl)amino]methyl}-5-4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate

[1056] Prepared from intermediates 4 and intermediate 89

Example 90

[1057]{2-methyl-4-[({2-{[methyl(2-phenylethyl)amino]methyl}-5-[4-trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid hydrochloride

[1058] Prepared by hydrolysis of example 89

[1059] m/z (M−H)⁻=568

[1060] HPLC Rt=3.5 minutes

Example 91

[1061]ethyl{2-methyl-4-[({2-{[methyl(pyridin-3-ylmethyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate

[1062] Prepared from intermediates 4 and 92

Example 92

[1063] {2-methyl4-[({2-{[methyl(pyridin-3-ylmethyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid hydrochloride

[1064] Prepared by hydrolysis of example 91

[1065] m/z (M−H)⁻=555

[1066] HPLC Rt=3.3 minutes

Example 93

[1067]ethyl{4-[({2-{[(3,5-dimethoxybenzyl)(methyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}acetate

[1068] Prepared from intermediates 4 and intermediate 91

Example 94

[1069]{4-[({2-{[(3,5-dimethoxybenzyl)(methyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid

[1070] Prepared by hydrolysis of example 93

[1071] m/z (M−H)⁻=614

[1072] HPLC Rt=3.5 minutes

Example 95

[1073]ethyl{4-[({4-{[cyclohexyl(methyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}acetate

[1074] Prepared from intermediates 4 and intermediate 90

Example 96

[1075]{4[({2-{[cyclohexyl(methyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid hydrochloride

[1076] Prepared by hydrolysis of example 95

[1077] m/z (M−H)⁻=46

[1078] HPLC Rt=3.4 minutes

Example 97

[1079]ethyl{4-[({3-[(isopropylthio)methyl]-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]-2-methylphenoxy}acetate

[1080] Prepared from intermediates 4 and 48

Example 98

[1081]{4-[({3-[(isopropylthio)methyl]-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]-2-methylphenoxy}aceticacid

[1082] Prepared by hydrolysis of example 97

[1083] m/z (M−H)⁻=525

[1084] HPLC Rt=4.7 minutes

Example 99

[1085]ethyl{2-methyl-4[({3-phenoxymethyl)-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}acetate

[1086] Prepared from intermediates 4 and 47

Example 100

[1087] {2-methyl4-[({3-(phenoxymethyl)-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid

[1088] Prepared by hydrolysis of example 99

[1089] m/z (M−H)⁻=543

[1090] HPLC Rt=4.6 minutes

Example 101

[1091]ethyl{4-[({3-[(benzylthio)methyl]-5-[4-trifluoromethyl)phenyl]thien-2-yl}methyl)thio]-2-methylphenoxy}acetate

[1092] Prepared from intermediates 4 and 46

Example 102

[1093]{4-[({3-[(benzylthio)methyl]-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]-2-methylphenoxy}aceticacid

[1094] Prepared by hydrolysis of example 101

[1095] m/z (M−H)⁻=573

[1096] HPLC Rt=4.7 minutes

Example 103

[1097]ethyl{2-methyl-4-[({3-{[4-(trifluoromethyl)phenoxy]methyl}-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}acetate

[1098] Prepared from intermediates 4 and 51

Example 104

[1099]{2-methyl-4-[({3-{[4-(trifluoromethyl)phenoxy]methyl}-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid

[1100] Prepared by hydrolysis of example 103

[1101] m/z (M−H)⁻=61 1

[1102] HPLC Rt=4.5 minutes

Example 105

[1103] ethyl{2-methyl-4-[({3-{[4-(2-phenylethyl)phenoxy]methyl}-5-[4(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}acetate

[1104] Prepared from intermediates 4 and 52

Example 106

[1105]{2-methyl-4-[({3-{[4-2-phenylethyl)phenoxy]methyl}-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid

[1106] Prepared by hydrolysis of example 105

[1107] m/z (M−H)⁻=648

[1108] HPLC Rt=4.80 minutes

Example 107

[1109]ethyl{2-methyl-4-[({3-{[(4′-methyl-1,1′-biphenyl-4-yl)oxy]methyl}-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}acetate

[1110] Prepared from intermediates 4 and 49:

Example 108

[1111]{2-methyl-4-[({3-{[(4′-methyl-1,1′-biphenyl-4-yl)oxy]methyl}-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid

[1112] Prepared by hydrolysis of example 107

[1113] m/z (M−H)⁻=633

[1114] HPLC Rt=4.8 minutes

Example 109

[1115]ethyl{2-methyl-4-[({3-{[methyl(phenyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}acetate

[1116] Prepared from intermediates 4 and 50

Example 110

[1117]{2-methyl-4-[({3-{[methyl(phenyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid

[1118] Prepared by hydrolysis of example 109

[1119] m/z (M−H)⁻=556

[1120] HPLC Rt=4.6 minutes

Example 111

[1121]ethyl{4-[({-ethyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]-2-methylphenoxy}acetate

[1122] Prepared from intermediates 4 and 53

Example 112

[1123]{4-[({3-ethyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]-2-methylphenoxy}aceticacid

[1124] Prepared by hydrolysis of example 111

[1125] m/z (M−H)⁻=465

[1126] HPLC Rt=4.4 minutes

Example 113

[1127]ethyl[4-[({2-methyl-5-[4-trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-(trifluoromethyl)phenoxy]acetate

[1128] To a mixture of zinc powder (0.357 g) in ethyl acetate (8 ml),stirred at 60° C., was addedethyl[4-(chlorosulfonyl)-2-(trifluoromethyl)phenoxy]acetate(intermediate 3, 0.5419) in portions. The reaction mixture was heateduntil the sulfonyl chloride had been consumed, thendichlorodimethylsilane (0.378 ml) was added drop-wise. The reaction wasstirred at reflux for 1 hour, then a solution of{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol (intermediate24, 0.40 g) in ethyl acetate (2 ml) was added and heating continued for18 hours. The reaction mixture was allowed to cool to room temperature,partitioned between brine and fresh ethyl acetate, dried over magnesiumsulfate, concentrated under reduced pressure. The residue was purifiedusing SPE (Si cartridge) using cyclohexane:ethyl acetate (40:1) aseluent to give the title compound as a pale brown gum.

[1129]¹H NMR (CDCl₃) δ 7.8 (d, 2H), 7.7 (d, 2H), 7.7 (d, 1H), 7.4 (d,d,1H), 6.8 (d, 1H), 6.65 (s, 1H), 4.70 (s, 2H), 4.26 (q, 2H), 3.80 (s,2H), 2.08 (s, 3H), 1.25 (t, 3H)

Example 114

[1130][4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-(trifluoromethyl)phenoxy]aceticacid

[1131] Prepared by hydrolysis of example 113

[1132] m/z (M−H)⁻=489

[1133] HPLC Rt=4.4 minutes

[1134] The following examples were prepared by an analogous method tothat described for the preparation of example 113 and 114

Example 115

[1135]ethyl[4-[({-5-[4-chlorophenyl]-2-methyl-3-furyl}methyl)thio]-2-(trifluoromethyl)phenoxy]acetate

[1136] Prepared from intermediates 3 and 32

Example 116

[1137][4-({[5-(4-chlorophenyl)-2-methyl-3-furyl]methyl}thio)-2-(trifluoromethyl)phenoxy]aceticacid

[1138] Prepared by hydrolysis of example 115

[1139] m/z (M−H)⁻=456

[1140] HPLC Rt=4.4 minutes

Example 117

[1141]ethyl(4-{2-[5-4-chlorophenyl)-2-methyl-3-furyl]ethenyl}-2-methylphenoxy)acetate

[1142] Sodium hydride (0.015 g, 60% dispersion in mineral oil) was addedto anhydrous ethanol (5 ml) followed by[4-(2-ethoxy-2-oxoethoxy)-3-methylbenzyl](triphenyl)phosphonium chloride(intermediate 17, 0.17 g) after 10 minutes. After a further 10 minutes5-4-chlorophenyl)-2-methyl-3-furaldehyde (intermediate 71, 0.082 g) wasadded and the reaction mixture stirred at ambient temperature for 20hours. The reaction mixture was treated with water and then the mixtureextracted with chloroform. The chloroform solution was separated with ahydrophobic frit and the excess aldehyde removed using 3-[4(hydrazinosulfonyl)phenyl]propionyl AM resin. The crude productremaining after this treatment was purified by Biotage® chromatographyusing a mixture of petroleum ether:ethyl acetate (9:1) as eluent to givethe title compounds.

Example 118

[1143]ethyl(4-{2-[5-(4-chlorophenyl)-2-methyl-3-furyl]ethyl}-2-methylphenoxy)acetate

[1144] A mixture ofethyl(4-{2-[5-(4-chlorophenyl)-2-methyl-3-furyl]ethenyl}2-methylphenoxy)acetate(intermediate 117, 0.070 g) and 10% palladium on carbon (0.070 g) inethyl acetate (10 ml) was stirred under a hydrogen atmosphere for 2hours. The reaction mixture was filtered through Celite™ and thefiltrate evaporated. The residue was purified by SPE (Si cartridge) andsequentially using petroleum ether; petroleum ether:ethyl acetate(50:1); petroleum ether:ethyl acetate (25:1); petroleum ether:ethylacetate (9:1) and petroleum ether:ethyl acetate (4:1) as eluents to givethe title compound.

Example 119

[1145]sodium(4-{2-[5-(4-chlorophenyl)-2-methyl-3-furyl]ethyl}-2-methylphenoxy)acetate

[1146] Prepared by hydrolysis of example 118:

[1147] A mixture ofethyl(4{2-[5-(4-chlorophenyl)-2-methyl-3-furyl]ethyl}2-methylphenoxy)acetate(0.030 g) in 1,4-dioxan (1.5 ml) was treated with 0.5M aqueous sodiumhydroxide (0.145 ml) and the reaction stirred at reflux for 5 hours. Thesolvent was removed to give a pale yellow solid which was trituratedwith ethyl acetate

[1148] m/z (M−H)⁻=383

[1149] HPLC Rt=4.70 minutes

[1150] The following examples were prepared by an analogous route tothat described for the preparation of example 119 (i.e examples117-119), where the sodium salt is isolated the above procedure isadopted. Where the free acid is isolated the hydrolysis procedure is asfor example 2

Example 120

[1151]Ethyl[2-methyl-4-(2-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethyl)phenoxy]acetate

[1152] Prepared from intermediates 17 and 74

Example 121

[1153][2-methyl-4-(2-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethyl)phenoxy]aceticacid

[1154] Prepared by hydrolysis of example 120

[1155] m/z (M−H)⁻=433

[1156] HPLC Rt=4.6 minutes

Example 122

[1157]ethyl[2-methyl-4-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)phenoxy]acetate

[1158] Prepared from intermediates 17 and 72

Example 123

[1159][2-methyl-4-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)phenoxy]aceticacid

[1160] Prepared by hydrolysis of example 122

[1161] m/z (M−H)⁻=417

[1162] HPLC Rt=4.4 minutes

Example 124

[1163]ethyl(4-{2-[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]ethyl}-2-methylphenoxy)acetate

[1164] Prepared from intermediates 17 and 73

Example 125

[1165]Sodium(4-{2-[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]ethyl}-2-methylphenoxy)acetate

[1166] Prepared by hydrolysis of example 124

[1167] m/z (M−H)⁻=437

[1168] HPLC Rt=4.6 minutes

Example 126

[1169]methyl3-[4-(2-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethyl)phenyl]propanoate

[1170] Prepared from intermediate 74 [4-(2-ethoxy-2-oxoethoxy)benzyl](triphenyl)phosphonium bromide (C. G Morgan et al., Biochim.Biophys. Acta 1982, 692(2), 196-201)

Example 127

[1171]3-[4-(2-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethyl)phenyl]propanoicacid

[1172] Prepared by hydrolysis of example 126

[1173] m/z (M−H)⁻=418

[1174] HPLC Rt=4.3 minutes

Example 128

[1175]ethyl[2-tert-butyl-6-methyl-4-(2-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethyl)phenoxy]acetate

[1176] Prepared from intermediates 74 and 15

Example 129

[1177][2-tert-butyl-6-methyl-4-(2-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethyl)phenoxy]aceticacid

[1178] Prepared by hydrolysis of example 128

[1179] m/z (M−H)⁻=490

[1180] HPLC Rt=4.7 minutes

Example 130

[1181]ethyl[2,6-dimethyl-4-(-2-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethyl)phenoxy]acetate

[1182] Prepared from intermediates 74 and 14

Example 131

[1183][2,6-dimethyl-4-2-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethyl)phenoxy]aceticacid

[1184] Prepared by hydrolysis of example 130

[1185] m/z (M−H)⁻=448

[1186] HPLC Rt=4.7 minutes

Example 132

[1187] ethyl3-[2-methyl-4-(2-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethyl)phenyl]propanoate

[1188] Prepared from intermediates 21 and 74

Example 133

[1189]3-[2-methyl-4-(2-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethyl)phenyl]propanoicacid

[1190] Prepared by hydrolysis of example 132

[1191] m/z (M−H)⁻=431

[1192] HPLC Rt=4.6 minutes

Example 134

[1193] ethyl3-[2-methyl-4-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)phenyl]propanoate

[1194] Prepared from intermediates 21 and 72

Example 135

[1195]3-[2-methyl-4-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)phenyl]propanoicacid

[1196] Prepared by hydrolysis of example 134

[1197] m/z (M−H)⁻=433

[1198] HPLC Rt=4.3 minutes

Example 136

[1199][2-methyl-4-({3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methoxy)phenoxy]aceticacid

[1200] A mixture ofethyl{4-[(5-bromo-3-methylthien-2-yl)methoxy]-2-methylphenoxy)acetate(intermediate 84, 0.20 g), 4-(trifluoromethoxy)benzeneboronic acid (0.11g), tetrakis(triphenylphosphine) palladium (0) (0.04 g) and sodiumcarbonate (0.138 g) in ethylene glycol dimethylether (10 ml) and water(10 ml) were heated at reflux for 2 hours. The reaction mixture wasconcentrated and the residue partitioned between 2M hydrochloric acidand ethyl acetate and extracted thrice into ethyl acetate. The organicsolutions were combined, dried with brine and over magnesium sulfate.

[1201] The product isolated after evaporation was further purified usingSPE (aminopropyl) and using ethyl acetate; methanol; 10% acetic acid inmethanol as eluents to give the title compound. Finally mass-directedautoprep was necessary to give the pure title compound as a white solid.

[1202] m/z (M−H)⁻=451

[1203] HPLC Rt=4.7 minutes The following example was prepared by ananalogous method to that described for example 134

Example 137

[1204][2-methyl-4-(2-{5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethoxy)phenoxy]aceticacid

[1205] Prepared from intermediate 70 and 4-trifluoromethylbenzeneboronic acid

[1206] m/z (M−H)⁻=436

[1207] HPLC Rt=4.1 minutes

Example 138

[1208]ethyl[2-methyl-4-({3-methyl-5-[6-(trifluoromethyl)pyridin-3-yl]thien-2-yl}methoxy)phenoxy]acetate

[1209] Prepared from intermediate 81 and5-bromo-2-trifluoromethylpyridine using an analogous method used for thepreparation of intermediate 78.

[1210] HPLC Rt4.2 minutes

Example 139

[1211][2-methyl-4-({3-methyl-5-[6-(trifluoromethyl)pyridin-3-yl]thien-2-yl}methoxy)phenoxy]aceticacid

[1212] Prepared by hydrolysis of example 138 m/z MH⁺=466

[1213] HPLC Rt=4.1 minutes

Example 140

[1214]ethyl(4-{[5-5-chloropyridin-2-yl)-3-methylthien-2-yl]methoxy}-2-methylphenoxy)acetate

[1215] Prepared from intermediate 81 and 2-bromo-5-chloropyridine usingan analogous method used for the preparation of intermediate 78.

Example 141

[1216]{4-{[5-(5-chloropyridin-2-yl)-3-methylthien-2-yl]methoxy}-2-methylphenoxy}aceticacid

[1217] Prepared by hydrolysis of example 140

[1218] m/z MH⁺=402

[1219] HPLC Rt=4.1 minutes

Example 142

[1220](4-{2-[5-(4-cyano-3-fluorophenyl)-3-methylthien-2-yl]ethyl}-2-methylphenoxy}aceticacid

[1221] A mixture of2-fluoro-4-[4-methyl-5-(2-{3-methyl-4-[(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)methoxy]phenyl}ethyl)thien-2-yl]benzonitrile(intermediate 101, 0.016 g) in 2-propanol (2 ml) was treated with 2Maqueous hydrochloric acid (1 ml) and the mixture stirred at reflux for 2hours. The solvent was removed and the residue dissolved in 1,4-dioxane(2 ml) and water (1 ml). This mixture was treated with 2M aqueous sodiumhydroxide (0.5 ml) and the mixture stirred for 16 hours). The solventwas removed and the residue purified by SPE (aminopropyl). The titlecompound, as the free acid, was recovered by treating a solution of thisproduct with Dowex H⁺.

[1222] m/z (M−H)⁻=408

[1223] HPLC Rt=4.3 minutes

Example 143

[1224]ethyl[4-(1,1-dimethyl-2-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethyl)-2-methylphenoxy]acetate

[1225] To a reactivial containingethyl[4-(1,1-dimethyl-2{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}-2-oxoethyl)-2-methylphenoxy]acetate(intermediate 106, 36 mg) was added trifluoroacetic acid (0.22 ml) andtriethylsilane (0.11 ml). The vial was then sealed and heated at 50° C.for 18 hours. The reaction was then allowed to cool to room andconcentrated in vacuo. Purification by flash column chromatographyeluting cyclohexane-1% EtOAc/cyclohexane yielded the title compound as acolourless oil.

[1226] HPLC Rt=4.5 minutes

[1227] m/z (MNH₄ ⁺) 508

Example 144

[1228][4-1,1-dimethyl-2-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethyl)-2-methylphenoxy]aceticacid

[1229] To a solution ofethyl[4-(1,1-dimethyl-2-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethyl)-2-methylphenoxy]acetate(Example 143, 0.03 g) in methanol (1 ml) and tetrahydrofuran (1 ml) wasadded 2M NaOH (0.5 ml). After 30 minutes stirring at room temperaturethe solvent was removed in vacuo. The residue was acidified with 2M HCland the product extracted into dichloromethane, the organic extract wasseparated by hydrophobic frit and the solvent removed in vacuo, to yieldthe title compound as a colourless gum.

[1230] LCMS Rt=4.5 minutes

[1231] m/z (M−H)⁻=461

Example 145

[1232]{2-ethyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[1233] To a mixture of zinc (407 mg) in ethyl acetate (10 ml) stirred at60° C. was added acetic acid (0.203 ml) followed by a solution ofethyl[4-(chlorosulfonyl)-2-ethylphenoxy]acetate (intermediate 111, 546mg) in ethyl acetate. The reaction mixture was stirred 60° C. for 2hours and then dichlorodimethylsilane (0.431 ml) was added drop-wise.After a further 90 minutes{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methanol (472 mg) wasadded and the reaction mixture stirred at reflux for 17 hours. Thereaction mixture was diluted with ethyl acetate; extracted with water,saturated aqueous sodium bicarbonate, water and dried with brine andover sodium sulfate. An attempt was purify the crude material byBiotage® chromatography using 3:2 petroleum ether: ethyl acetate aseluent. The partially purified material (223 mg) was hydrolyzed in1,4-dioxan (6 ml) using 0.5 M aqueous sodium hydroxide (1.86 ml) for 16hours. The reaction mixture was neutralized with 50W×2-200 Dowex;evaporated and the residue purified by mass-directed autopreparativeHPLC to give the title compound as a solid.

[1234] LCMS Rt=4.3 minutes

[1235] m/z (M−H)⁻=449

Example 146

[1236]{2-isopropyl-4-[({2-methyl-5-[4-trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[1237] The title compound was prepared usingethyl[4-(chlorosulfonyl)-2-isopropylphenoxy]acetate (intermediate 112)by a method analogous to that used for the preparation of{2-ethyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl)methyl)thio]phenoxy}aceticacid (example 145).

[1238] LCMS Rt=4.30 minutes

[1239] m/z (M−H)⁻=463

Example 146

[1240]{2-chloro-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[1241] The title compound was prepared fromethyl[4-(chlorosulfonyl)-2-chlorophenoxy]acetate (intermediate 113) by amethod analogous to that used for the preparation of{2-ethyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid (example 145).

[1242] LCMS Rt=4.30 minutes

[1243] m/z (M−H)⁻=454

Example 147

[1244]{2-bromo-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[1245] The title compound was prepared fromethyl[4-(bromosulfonyl)-2-chlorophenoxy]acetate (intermediate 114) by amethod analogous to that used for the preparation of{2-ethyl[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid (example 145).

[1246] LCMS Rt=4.20 minutes

[1247] m/z (M−H)⁻=502

Example 148

[1248]ethyl{2-methyl-4-[({3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methyl)thio]phenoxy}acetate

[1249] The title compound was prepared by a method analogous to thatused for the preparation ofethyl{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate(example 1) using ethyl(4-mercapto-2-methylphenoxy)acetate (intermediate4) and {3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methanol(intermediate 118).

[1250] LCMS Rt=4.4 minutes

[1251] m/z (MH)⁺=497

Example 149

[1252]{2-methyl-4-[({3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid

[1253] The title compound was prepared by using a method analogous tothat used for the preparation of2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid (example 2) using ethyl{2-methyl-4-[({3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methyl)thio]phenoxy}acetate(example 148).

[1254] LCMS Rt=4.4 minutes

[1255] m/z (M−H)⁻=467

Example 150

[1256]ethyl[4-({5-[2,5-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)-2-methylphenoxy]acetate

[1257] The title compound was prepared by a method analogous to thatused for the preparation ofethyl{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate(example 1) using ethyl(4-hydroxy-2-methylphenoxy)acetate (intermediate7) and{5-[2,5-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl)methanol(intermediate 120).

[1258] LCMS Rt=4.3 minutes

[1259] m/z (MH)⁺=518

Example 151

[1260][4-(5-[2,5-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)-2-methylphenoxy]aceticacid

[1261] The title compound was prepared by using a method analogous tothat used for the preparation of2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid (example 2) usingethyl[4-({5-[2,5-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)-2-methylphenoxy]acetate(example 150)

[1262] LCMS Rt=4.6 minutes

[1263] m/z (M−H)⁻=471

Example 152

[1264]ethyl[4-({5-[2,3-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)-2-methylphenoxy]acetate

[1265] The title compound was prepared by a method analogous to thatused for the preparation ofethyl{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate(example 1) using ethyl(4-hydroxy-2-methylphenoxy)acetate (intermediate7) and{5-[2,3-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methanol(intermediate 122).

[1266] LCMS Rt=4.3 minutes

[1267] m/z (MH)⁺=501

Example 153

[1268]ethyl[4-({5-[2,3-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)-2-methylphenoxy]acetate

[1269] The title compound was prepared by using a method analogous tothat used for the preparation of2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid (example 2) usingethyl[4-({5-[2,3-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)-2-methylphenoxy]acetate(example 152).

[1270] LCMS Rt=4.6 minutes

[1271] m/z (M−H)⁻=471

Example 154

[1272]ethyl[4-({5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)-2-methylphenoxy]acetate

[1273] The title compound was prepared by a method analogous to thatused for the preparation ofethyl{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate(example 1) using ethyl(4-hydroxy-2-methylphenoxy)acetate (intermediate7) and{5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methanol(intermediate 124).

[1274] LCMS Rt=4.3 minutes

[1275] m/z (MNH)⁺=500

Example 155

[1276][4-({5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)-2-methylphenoxy]acetate

[1277] The title compound was prepared by using a method analogous tothat used for the preparation of2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid (example 2) usingethyl[4-({5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)-2-methylphenoxy]acetate(example 154).

[1278] LCMS Rt=4.3 minutes

[1279] m/z (M−H)⁻=453

Example 156

[1280]ethyl[2-methyl-4-(1-{5-[4-(trifluoromethyl)phenyl]thien-3-ylethoxy)phenoxy]acetate

[1281] The title compound was prepared by a method analogous to thatused for the preparation ofethyl{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate(example 1) using ethyl(4-hydroxy-2-methylphenoxy)acetate (intermediate7) and 1-5-[4-(trifluoromethyl)phenyl]thien-3-yl}ethanol (intermediate126).

[1282] LCMS Rt=4.2 minutes

[1283] m/z (MNH₄)⁺=482

Example 157

[1284][2-methyl-4-(1-{5-[4-(trifluoromethyl)phenyl]thien-3-yl}ethoxy)phenoxy]aceticacid

[1285] The title compound was prepared by using a method analogous tothat used for the preparation of2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid (example 2) usingethyl[2-methyl-4-(1-{5-[4-(trifluoromethyl)phenyl]thien-3-yl}ethoxy)phenoxy]acetate(example 156).

[1286] LCMS Rt=4.1 minutes

[1287] m/z (M−H)⁻=435

Example 158

[1288]ethyl[2-methyl-4-(phenyl{5-[4-trifluoromethyl)phenyl]thien-3-yl}methoxy)phenoxy]acetate

[1289] The title compound was prepared by a method analogous to thatused for the preparation ofethyl{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate(example 1) using ethyl(4-hydroxy-2-methylphenoxy)acetate (intermediate7) and phenyl{5-[4-(trifluoromethyl)phenyl]thien-3-yl}methanol(intermediate 127).

[1290] LCMS Rt=4.3 minutes

[1291] m/z (MNH₄)⁺=544

Example 159

[1292][2-methyl-4-(phenyl{5-[4-(trifluoromethyl)phenyl]thien-3-yl}methoxy)phenoxy]aceticacid

[1293] The title compound was prepared by using a method analogous tothat used for the preparation of2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl)methyl)thio]phenoxy}aceticacid (example 2) usingethyl[2-methyl-4-(phenyl{5-[4-(trifluoromethyl)phenyl]thien-3-yl}methoxy)phenoxy]acetate(example 158).

[1294] LCMS Rt=4.3 minutes

[1295] m/z (M−H)⁻=497

Example 160

[1296] ethyl2-methyl-2-[2-methyl-4-(phenyl{5-[4-(trifluoromethyl)phenyl]thien-3-yl}methoxy)phenoxy]propanoate

[1297] The title compound was prepared by a method analogous to thatused for the preparation ofethyl{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate(example 1) using ethyl 2-(4-hydroxy-2-methylphenoxy)-2-methylpropanoate(intermediate 10) andphenyl{5-[4-(trifluoromethyl)phenyl]thien-3-yl}methanol (intermediate127).

[1298] LCMS Rt=4.5 minutes

[1299] m/z (MNH₄)⁺=572

Example 161

[1300]2-methyl-2-[2-methyl-4-(phenyl{5-[4-(trifluoromethyl)phenyl]thien-3-yl}methoxy)phenoxy]propanoicacid

[1301] The title compound was prepared by using a method analogous tothat used for the preparation of2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid (example 2) using ethyl2-methyl-2-[2-methyl-4-(phenyl{5-[4-(trifluoromethyl)phenyl]thien-3-yl}methoxy)phenoxy]propanoate(example 160).

[1302] LCMS Rt=4.3 minutes

[1303] m/z (M−H)⁻=525

Example 162

[1304]Ethyl[2-methyl-4-(1-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethoxy)phenoxy]aceticacid

[1305] The title compound was prepared by a method analogous to thatused for the preparation ofethyl{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate(example 1) using ethyl(4-hydroxy-2-methylphenoxy)acetate (intermediate7) and 1-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethanol(intermediate 130).

[1306] LCMS Rt=4.4 minutes

Example 163

[1307][2-methyl-4-(1-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethoxy)phenoxy]aceticacid

[1308] The title compound was prepared by using a method analogous tothat used for the preparation of2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid (example 2) usingethyl[2-methyl-4-(1-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethoxy)phenoxy]aceticacid (example 162).

[1309] LCMS Rt=4.0 minutes

[1310] m/z (M−H)⁻=449

[1311] Examples 163-168 were prepared using intermediates 133-138respectively by methods analogous to those described above for thepreparation of example 63

Example 163

[1312]ethyl[4-({3-[(isopropylthio)methyl]-5-[4-trifluoromethyl)phenyl]thien-2-yl}methoxy)-2-methylphenoxy]acetate

[1313] R_(f)=0.33 (chloroform)

Example 164

[1314]ethyl{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-[(2,3,6-trimethylphenoxy)methyl]thien-2-yl}methyl)thio]phenoxy}acetate

[1315] R_(f)=0.56 (chloroform)

Example 165

[1316]ethyl{4-[({3-{[(2-isopropyl-6-methylpyrimidin-4-yl)oxy]methyl}-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]-2-methylphenoxy}acetate

[1317] HPLC Rt=4.5 minutes

[1318] m/z MH⁺=631

Example 166

[1319]ethyl{2-methyl-4-[({2-[(quinolin-2-ylthio)methyl]5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate

[1320] HPLC Rt=4.7 minutes

Example 167

[1321]ethyl{2-methyl-4-[({2-4[{(3-phenyl-1H-1,2,4-triazol-5-yl)thio]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate

[1322] HPLC Rt=4.4 minutes

Example 168

[1323]ethyl{4-[({2-{[4-(4-methoxyphenyl)piperazin-1-yl]methyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}acetate

[1324]¹H NMR (CDCl3) δ 7.73 (d, 2H), 7.62 (d, 2H), 7.24 (d, 1H), 7.16(dd, 1H), 6.85 (m, 4H), 6.69 (s, 1H), 6.60 (d, 1H), 4.61 (s, 2H), 4.25(bs, 4H)), 2.04 (s, 3H)), 1.28 (t, 3H)

[1325] Examples 169-174 were prepared using examples by hydrolysis ofthe ethyl esters (examples 163-168).

Example 169

[1326][4-(13-[(isopropylthio)methyl]-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)-2-methylphenoxy]aceticacid

[1327] HPLC Rt=4.4 minutes

[1328] m/z (M−H)⁻=509

Example 170

[1329]{2-methyl-4-[({5-[4-trifluoromethyl)phenyl]-3-[(2,3,6-trimethylphenoxy)methyl]thien-2-yl}methyl)thio]phenoxy}aceticacid

[1330] HPLC Rt=4.7 minutes

[1331] m/z (M−H)⁻=585

Example 171

[1332]{4-[({3-{[(2-isopropyl-6-methylpyrimidin-4-yl)oxy]methyl}-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]-2-methylphenoxy}aceticacid

[1333] HPLC Rt=4.6 minutes

[1334] m/z (M−H)⁻=601

Example 172

[1335]{2-methyl-4-[({-2-[(quinolin-2-ylthio)methyl]-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[1336] HPLC Rt=4.7 minutes

[1337] m/z (M−H)-594

Example 173

[1338]{2-methyl-4[({2-{[(3-phenyl-1H-1,2,4-triazol-5-yl)thio]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid

[1339] HPLC Rt=4.3 minutes

[1340] m/z (M−H)⁻=610

Example 174

[1341]{4-[({2-{[4-(4-methoxyphenyl)piperazin-1-yl]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid

[1342] HPLC Rt=3.6 minutes

[1343] m/z MH⁺=625

[1344] The following intermediates and ligands were prepared for thebinding and transfection assays described below:

[1345] The following intermediates and ligands were prepared for thebinding and transfection assays described below:

[1346] (i)2-{2-methyl-4-[({4-methyl-2-[4-trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}aceticacid.

[1347] This compound was used as a PPARdelta reference in thetransfection assays described below and was prepared according to thefollowing method:

[1348] To a well stirred solution of LiAlH₄ (1.52 g, 40 mmol) in dry THF(50 mL) at 0° C., was slowly added a solution of ethyl4-methyl-2-[4-(trifluoromethyl)phenyl)-thiazole-5-carboxylate (12.6 g,40 mmol) in dry THF (50 mL). The mixture was stirred at room temperaturefor 2 hs. The reaction was quenched by slow addition at 0° C. of water(2 mL), 5N NaOH (2 mL) and water (6 mL). The precipitate was filtered,washed with EtOAc, MeOH, CH₂Cl₂ and THF. After evaporation, a yellowsolid was obtained, that was crystallyzed from MeOH-water to affordintermediate 1 depicted above (9.90 g, 36 mmol, 90%) as a yellow solidmp 120-122° C.

[1349] To a cold (0° C.) stirred solution of intermediate 1 (8.2 g, 30mmol) and Et3N (6.07 g, 8.36 mL, 60 mmol), in dry CH₂Cl₂ (120 mL) wasslowly added MeSO₂Cl (5.49 g, 3.71 mL, 48 mmol). After 2 hs at 0° C.more Et3N (6 mmol) and MeSO₂Cl (4.8 mmol) were added. After 2 more h atic (hexane:EtOAc, 1:1) showed complete reaction. The reaction mixturewas diluted with CH₂Cl₂ (120 mL) and washed with NaHCO₃ (sat.) (2×240mL) and water (2×240 mL), dried, filtered and evaporated to affordintermediate 2 (8.0 g, 27 mmol, 90%) as a yellow solid.

[1350] A mixture of methyl bromoacetate (3.80 g, 2.35 mL, 25.0 mmol),4-hydroxy-3-methylacetophenone (4.13 g, 27.5 mmol), and Cs₂CO₃ (17.9 g,55 mmol) in dry acetonitrile (125 mL) was stirred overnight at r.t. Themixture was filtered, washed with acetonitrile, and the solventevaporated. The remaining syrup was redissolved in EtOAc (400 mL),washed with 1N NaOH (3×400 mL) and water (2×400 mL), dried, filtered,and evaporated to afford the pure title compound (5.50 g, 24.7 mmol,99%) as a white solid.

[1351] A solution of Intermediate 3 (5.33 g, 24 mmol), mCPBA (7.25 g, 42mmol) and p-TsOH (480 mg) in dry dichloromethane (120 mL) was refluxedfor 48 h. The reaction mixture was diluted with dichloromethane (120mL), and successively washed with: aq. KI (2×200 mL), NaHSO₃ (2×200 mL),dried, filtered and evaporated to afford the title compound (5.0 g, 21mmol, 87%) as a syrup.

[1352] A solution of intermediate 4 (4.76 g, 20 mmol) in dry methanol(180 mL) was treated with a 0.5 N solution of NaOCH₃ in MeOH (40 mL, 20mmol). After 1 h at r.t., the solution was neutralized with 1N HCl (20mL). The solvent was evaporated, and the residue partitioned betweendichloromethane (300 mL) and water (300 mL). The organic solution wasseparated, washed with water (300 mL), dried, filtered, and evaporatedto afford the title compound (3.3 g, 16.8 mmol, 84%) as a brown solid.

[1353] Intermediate 2 and intermediate 5 were coupled as in dryacetonitrile (5.0 mL) was stirred overnight at room temperature. Thereaction mixture was diluted with CH₂Cl₂— (50 mL) and water (50 mL). Theorganic phase was separated and further washed with 1N NaOH (2×50 mL),and water (3×50 mL), dried, filtered, and evaporated to afford the finalproduct (87%) as brown solid.

[1354]2-{2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}aceticacid

[1355] Intermediate 6 was hydrolyzed as described below. A solution ofthe corresponding ester (1 mmol) in THF (10 mL) (in some cases few dropsof MeOH were added to help solubility), was treated with 1N LiOH inwater (2 mL, 2 mmol), and stirred 16 h at room temperature (whenreactions were slow, the temperature was elevated to 50° C.). Thesolution was neutralized with 1N HCl (2 mL, 2 mmol) and the organicsolvent evaporated to afford an aqueous solution with an insolubleproduct. If the insoluble was a solid, it was filtered and dried toafford the final product. If the insoluble was an oil, it was extractedwith EtOAc (30 mL). The organic solution was separated, washed withwater (2×30 mL), dried, filtered, and evaporated to afford the finalproduct.

[1356] The crude material was crystallized from MeOH:water to afford thetitle compound (60%) as yellow solid: mp 139-141° C.

[1357] Anal. Calcd. for C₂₁H₁₈NO₃F₃S₂: C, 55.62; H, 4.00; N, 3.09; S,14.14. Found: C, 55.52; H, 4.11; N, 3.13; S, 14.29.

[1358] (ii)2-methyl-2-[4-{[(4-methyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}-phenoxy]propionic acid.

[1359] This compound was used as a PPAR alpha reference in thetransfection assay described below and was prepared according to thefollowing method.

[1360] Intermediate A:

[1361] Same procedure as Stout, D. M. J. Med. Chem. 1983, 26(6), 808-13.To 4-methoxybenzyl amine (25 g, 0.18 mol; Aldrich) was added 46% HBr inH₂O (106 ml, 0.9 mol; Aldrich). The reaction was refluxed overnight,then the reaction cooled to 0° C. and neutralized to pH7 slowly withKOH(s). The reaction is allowed to stir for −30 min, then the solidfiltered and dried. The solid redisolved in hot MeOH, filtered and thesolution cooled to afford 19 g (85%) intermediate A.

[1362]¹H NMR (DMSO-d₆): δ 8.0 (bs, 1H), 7.2 (d, 2H), 6.75 (d, 2H), 3.85(s, 2H), 3.50 (bs, 2H).

[1363] Intermediate 2:

[1364] A solution of ethyl 2-chloroacetoacetate (35.3 g, 29.7 mL, 0.21mol) and 4-(trifluoromethyl)thiobenzamide (44 g, 0.21 mol) in EtOH (300mL) was refluxed overnight. After cooling to room temperature thesolvent removed in vacuo. The final product (intermediate 2) wasrecrystallized from a minimum of MeOH to afford 40 g (59%) of finalproduct as a white solid. ¹H NMR (CDCl₃): δ 8.10 (d, 2H), 7.70 (d, 2H),4.40 (q, 2H), 2.80 (s, 3H), 1.4 (t, 3H).

[1365] Intermediate 3:

[1366] To intermediate 2 (1.84 g, 5.8 mmol) in THF was added 1N LiOH (6mL, 6 mmol) and the reaction stirred at rt. After −3 h, the reactionneutralized with 1N HCl, extracted 3×100 mL EtOAc, dried over Na₂SO₄,filtered and the solvent removed under vaccum to afford 1.5 g (89%)intermediate 3 as a white solid. ¹H NMR (DMSO-d₆): δ 13.55 (bs, 1H),8.25 (d, 2H), 7.95 (d, 2H), 2.75 (s, 3H).

[1367] Intermediate 4:

[1368] To intermediate 3 (1 g, 7 mmol) in CH₂Cl₂/DMF (1:1) was addedHOBT (565 mg, 4.2 mmol; Aldrich), EDC (800 mg, 4.2 mmol; Aldrich) andintermediate 1 (860 mg, 7 mmol). The reaction stirred at rt for 18 h.The solvent removed in vacuo, treated with H₂O and extracted 3×100 mLCH₂Cl₂. The organic phases combined and washed with 1N HCl, dried overNa₂SO₄, filtered and evaporated to afford a mixture (N-substituted andN,O-substituted). The mixture disolved in MeOH and treated with 1N NaOH.The reaction stirred 18 h at 50° C. The solvent removed in vacuo,dissolved in CH₂Cl₂, washed with H₂O, and dried over Na₂SO₄. The solventevaporated the residue chromatographed (CH₂Cl₂/MeOH: 99/1) to afford 610mg (47%) of intermediate 4 as a white solid. ¹H NMR (DMSO-d₆): δ 9.30(s, 1H), 8.80 (t, 1H), 8.20 (d, 2H), 6.70 (d, 2H), 4.35 (d, 2H), 2.6 (s,3H).

[1369] Intermediate 5:

[1370]2-methyl-2-[4-{[(4-methyl-2-[4-trifluoromethylphenyl]thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionicacid ethyl ester

[1371] To intermediate 4 (710 mg, 1.81 mmol) in DMF (50 mL) was addedthe K₂CO₃ (275 mg, 1.99 mmol) followed by the ethyl2-bromo-2-methylpropanate (280 μL, 1.91 mmol; Aldrich) and the reactionheated to 80° C. After 18 h, the reaction cooled to rt and the solventremoved in vacuo. The residue treated with water (200 mL), extracted3×50 mL CH₂Cl₂, dried over Na₂SO₄, filtered and the solvent removedunder vaccum. The residue was chromatographed (CH₂Cl₂/MeOH: 99/1). Toafford 680 mg (77%) of Intermediate 5 as a clear oil. ¹H NMR(CDCl₃): δ7.95 (d, 2H), 7.60 (d, 2H), 7.15 (d, 2H), 6.75 (d, 2H), 6.05 (t, 1H),4.45 (d, 2H), 4.15 (q, 2H), 2.65 (s, 3H), 1.50 (s, 6H), 1.20 (t, 3H).

[1372]2-methyl-2-[4-{[(4-methyl-2-[trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionicacid

[1373] To Intermediate 5 (680 mg, 1.39 mmol) in MeOH was added 1N NaOH(1.6 mL, 1.6 mmol) and the reaction stirred at 60° C. After 18 h, thereaction cooled to rt and the solvent evaporated. The residue treatedwith 1N HCl, extracted 3×20 mL THF and the solvent removed under vacuum.500 mg (75%) The title compound was precipitated as a white solid from aminimum CH₂Cl₂ and pentane. mp: changes the form between 60-70° C.;LC/MS (m/z): 477.22 (100%, AP−), 479.12 (100%, AP+); anal.C₂₃H₂₁F₃N₂O₄S: C 5.71 (57.73), H 4.56 (4.42), N 5.77 (5.85), S 6.15(6.70).

[1374] Binding Assay:

[1375] Compounds were tested for their ability to bind to hPPAR gammahPPAR alpha, or PPAR delta using a Scintillation Proximity Assay (SPA).The PPAR ligand binding domain (LBD) was expressed in E. coli as polyHistagged fusion proteins and purified. The LBD was then labeled withbiotin and immobilized on streptavidin-modified scintillation proximitybeads. The beads were then incubated with a constant amount of theappropriate radioligand (³H-BRL 49653 for PPAR gamma, radiolabelled2-(4-(2-(2,3-Ditritio-1-heptyl-3-(2,4-difluorophenyl)ureido)ethyl)phenoxy)-2-methylbutanoicacid for hPPAR alpha (see WO 00/08002) and labelled GW 2433 (see Brown,P. J et al. Chem. Biol. 1997, 4, 909-918. For the structure andsynthesis of this ligand) for PPAR delta) and variable concentrations oftest compound, and after equilibration the radioactivity bound to thebeads was measured by a scintillation counter. The amount of nonspecificbinding, as assessed by control wells containing 50 FM of thecorresponding unlabeled ligand, was subtracted from each data point. Foreach compound tested, plots of ligand concentration vs. CPM ofradioligand bound were constructed and apparent K, values were estimatedfrom nonlinear least squares fit of the data assuming simple competitivebinding. The details of this assay have been reported elsewhere (see,Blanchard, S. G. et. al. Development of a Scintillation Proximity Assayfor Peroxisome Proliferator-Activated Receptor gamma Ligand BindingDomain. Anal. Biochem. 1998, 257, 112-119).

[1376] Transfection Assay:

[1377] Compounds were screened for functional potency in transienttransfection assays in CV-1 cells for their ability to activate the PPARsubtypes (transactivation assay). A previously established chimericreceptor system was utilized to allow comparison of the relativetranscriptional activity of the receptor subtypes on the same targetgene and to prevent endogenous receptor activation from complicating theinterpretation of results. See, for example, Lehmann, J. M.; Moore, L.B.; Smith-Oliver, T. A.; Wilkison, W. O.; Willson, T. M.; Kliewer, S.A., An antidiabetic thiazolidinedione is a high affinity ligand forperoxisome proliferator-activated receptor γ (PPARγ), J. Biol. Chem.,1995, 270, 12953-6. The ligand binding domains for murine and human PPARalpha, PPAR gamma, and PPAR delta were each fused to the yeasttranscription factor GAL4 DNA binding domain. CV-1 cells weretransiently transfected with expression vectors for the respective PPARchimera along with a reporter construct containing five copies of theGAL4 DNA binding site driving expression of secreted placental alkalinephosphatase (SPAP) and β-galactosidase. After 16 h, the medium wasexchanged to DME medium supplemented with 10% delipidated fetal calfserum and the test compound at the appropriate concentration. After anadditional 24 h, cell extracts were prepared and assayed for alkalinephosphatase and β-galactosidase activity. Alkaline phosphatase activitywas corrected for transfection efficiency using the β-galactosidaseactivity as an internal standard (see, for example, Kliewer, S. A., et.al. Cell 83, 813-819 (1995)). Rosiglitazone (BRL 49653) was used as apositive control in the hPPAR gamma assay. The positive control in thehPPAR alpha assays was2-methyl-2-[4-[(4-methyl-2-[4-trifluoromethylphenyl]-thiazol-5-yl-carbonyl)amino]methyl)phenoxy]propionicacid. The positive control for PPAR delta assays was2-{2-methyl-4-[({4-methyl-2-{trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}aceticacid.

What is claimed is:
 1. A compound of formula (I) or pharmaceuticallyacceptable salts and solvates thereof.

wherein X¹ is O, S, NH or NCH₃, C₁₋₃alkyl. R¹ and R² are independently Hor C₁₋₃alkyl. R³, R⁴ and R⁵ are independently H, CH₃, OCH₃, CF₃ orhalogen; R²⁶ and R²⁷ are independently H, C₁₋₃ alkyl or an R²⁶ and R²⁷may, together with the carbon atom to which they are bonded form a 3-5membered cycloalkyl ring; m is 0-3; X² is (CR¹⁰R¹¹)_(n), O, S, OCH₂; n=1or 2; R⁶, R⁷, R¹⁰ and R¹¹ independently represent H, F, C₁₋₆alkyl,phenyl or allyl or form a double bond as indicated by the depicteddashed line; one of Y and Z is CH, the other is S or O with the provisothat Y cannot be substituted and Z can only be substituted when it iscarbon. R⁸ is phenyl or pyridyl (wherein the N is in position 2 or 3)either of which may optionally be substituted by one or more halogen,CF₃, OCF₃, C₁₋₆ straight or branched alkyl with the provision that whenR³ is pyridyl, the N is unsubstituted. R⁹ is C₁₋₄ alkyl, CF₃ or —CH₂D,wherein D is selected from:

wherein R¹² is selected from the group consisting of moieties depictedbelow.

R¹⁷ and R¹⁸ are independently hydrogen C₁₋₆alkyl, C₁₋₆perfluoroalkyl,C₁₋₆acyl, —OC₁₋₆alkyl, perfluoroOC₁₋₆alkyl, or 1-hydroxyC₁₋₆alkyl; R¹⁹is C₁₋₆alkyl; R²² is C₁₋₆alkyl, 6-memberedaryl, 5-membered heteroaryl,—C₁₋₆alkylenearyl; R²³ is C₁₋₆alkyl, C₁₋₆cycloalkyl, 6-membered aryl ora 5-membered heteroaryl optionally substituted with one or twosubstituents selected from perfluroC₁₋₆alkyl, perfluroOC₁₋₆alkyl,C₁₋₆alkyl, —OC₁₋₆alkyl and —SC₁₋₆alkyl; and. R²⁴ is C₁₋₆alkyl,—C₁₋₆alkylenearylC₁₋₆alkylaryl, or a 6-membered aryl optionallysubstituted with one or two substituents selected from perfluroC₁₋₆alkylperfluroOC₁₋₆alkyl, C₁₋₆alkyl, —OC₁₋₆alkyl, and —SC₁₋₆alkyl;

where Z is O, N or S (note that when Z is N, the depicted bond can beattached to the nitrogen in the ring as well as any of the carbons inthe ring);

R²⁰ is C₁₋₆alkyl, 6 membered aryl, —OC₁₋₆alkyl, hydroxy or 1-alkoxyC₁₋₆alkyl.

where R¹³ and R¹⁴ are independently halogen, a 6-membered aryl or a5-membered heteroaryl optionally substituted with one or twosubstituents selected from perfluroC₁₋₆alkyl, perfluroOC₁₋₆alkyl,C₁₋₆alkyl, —OC₁₋₆alkyl, and —SC₁₋₆alkyl;

R²¹ is C₁₋₃-alkyl, —C₁₋₆alkylenephenyl, 6-membered aryl, optionallysubstituted with one or two substituents selected from CN, 5 or6-membered heteroaryl, bicyclic aryl or bicyclic heteroaryl,perfluroC₁₋₆alkyl, perfluroOC₁₋₆alkyl, C₁₋₆alkyl, —OC₁₋₆alkyl and—SC₁₋₆alkyl.

R¹⁵ and R¹⁶ are independently C₁₋₆alkyl, C₃₋₆cycloalkyl, C₀₋₆alkylene6-membered aryl optionally substituted with 1 or 2 C₁₋₃alkyl or alkoxygroups, C₀₋₆alkylene 5-membered heteroaryl, pyridyl, bicyclic aryl orbicyclic heteroaryl or R¹² as defined above.

—(CH₂)_(n)—R²⁸  I wherein n is 1 or 3, R²⁸ is 6 membered aryl, 5 or 6membered heteroaryl or bicyclic aryl or bicyclic heteroaryl. —O—R²¹  J—S—R²¹  K wherein R²¹ is defined above.
 2. A compound according to claim1 wherein R²⁶ and R²⁷ are independently H or CH₃.
 3. A compoundaccording to claim 2 wherein R²⁶ and R²7 are both H.
 4. A compoundaccording to claims 1-3 wherein M is O.
 5. A compound according toclaims 14 wherein X¹ is O or S.
 6. A compound according to claims 1-5wherein X² is C(R¹⁰R¹¹)_(n), O or S.
 7. A compound according to claim 6wherein n is
 1. 8. A compound according to claims 1-7 wherein R⁶, R⁷,R¹⁰ and R¹¹ are H.
 9. A compound according to any preceding claimwherein R⁸ is phenyl optionally substituted by 1, 2, 3, 4, or 5substituents independently selected from CH₃, OCH₃, CF₃, or halogen. 10.A compound according to claim 9 wherein the phenyl group ismonosubstituted.
 11. A compound according to claim 10 wherein thecompound is monosubstitued in the para position.
 12. A compoundaccording to claim 11 wherein the substituent is CF₃.
 13. A compoundaccording to any preceding claim wherein R³ is H, CH₃ or CF₃.
 14. Acompound according to claim 13 wherein R³ is CH₃.
 15. A compoundaccording to claim 14 wherein R⁴ and R⁵ are H.
 16. A compound accordingto any preceding claim wherein R⁹ is C₁₋₆alkyl, CF₃, CH₂D wherein D isselected from moieties G, H, I, J and K.
 17. A compound according toclaim 1 selected from:{4-[({3-ethyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]-2-methylphenoxy}aceticacid[4-({[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]methyl}thio)-2-methylphenoxy]aceticacid[2-methyl-4-({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)phenoxy]aceticacid{2-methyl-4-[({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid{2-methyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid{2-ethyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid{2-isopropyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid[2-methyl-4-({3-methyl-5[4-(trifluoromethoxy)phenyl]thien-2-yl}methoxy)phenoxy]aceticacid{4-[({2-[(benzylthio)methyl]-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid{2-methyl-4-[({3-methyl-5-[4-(trifluoromethyl)phenyl]-2-furyl}methyl)thio]phenoxy}aceticacid{2-methyl-4-[({3-methyl-4-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid[4-({[5-(4-chlorophenyl)-2-methyl-3-furyl]methyl}thio)-2-methylphenoxy]aceticacid{2-methyl-4-[({2-(trifluoromethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid[2-methyl-4-(2{4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl)ethyl)phenoxy]aceticacid[2-methyl-4-(2{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethyl)phenoxy]aceticacid(4-{2-[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]ethyl)₂-methylphenoxy}aceticacid3-[4-({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)phenyl]propanoicacid{2-methyl-4-[({3-(phenoxymethyl)-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid3-[2-methyl-4-[({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)phenyl]propanoicacid{4-[({2-[(benzylthio)methyl]-5-[4-(trifluoromethyl)phenyl]-3-furyl)methyl)thio]-2-methylphenoxy}aceticacid{4-[({2-[(isopropylthio)methyl]-5-[4-(trifluoromethyl)phenyl]-3-furyl)methyl)thio]-2-methylphenoxy}aceticacid{2-methyl-4-[({2-{[methyl(phenyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid[2-methyl-4-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)phenoxy]aceticacid3-[2-methyl-4-(2-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethyl)phenyl]propanoicacid[2-methyl-4-({2-methyl-5[4-(trifluoromethyl)phenyl]thien-3-yl}methoxy)phenoxy]aceticacid{4-[({2-isopentyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid{2-methyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]thien-3-yl}methyl)thio]phenoxy}aceticacid[4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-(trifluoromethyl)phenoxy]aceticacid{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-2-furyl}methyl)thio]phenoxy}aceticacid{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]thien-3-yl}methyl)thio]phenoxy}aceticacid{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid[4-({[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]methyl}thio)-2-methylphenoxy]aceticacid(4-{[5-(4-chlorophenyl)-2-methyl-3-furyl]methoxy}-2-methylphenoxy}aceticacid[2-methyl-4-({2-(trifluoromethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenoxy]aceticacid[2-methyl-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methoxy)phenoxy]aceticacid[2-methyl-4-({3-methyl-5-4-(trifluoromethyl)phenyl]-2-furyl}methoxy)phenoxy]aceticacid3-(4-{[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]methoxy}phenyl)propanoicacid(4-[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]methoxy)₂-methylphenoxy}aceticacid[4-({[5-(4-chlorophenyl)-2-methyl-3-furyl]methyl}thio)-2-(trifluoromethyl)phenoxy]aceticacid{4-[({3-[(isopropylthio)methyl]-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]-2-methylphenoxy}aceticacid{4-[({3-[(benzylthio)methyl]-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]-2-methylphenoxy}aceticacid3-(4-[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]methoxy}-2-methylphenyl)propanoicacid{2-methyl-4-[({2-(phenoxymethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid3-[2-methyl-4-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)phenyl]propanoicacid{2-methyl-4-[({3{[4-(trifluoromethyl)phenoxy]methyl}-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid{4-[({2-{[(2-furyl}methyl)thio]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid{2-methyl-4-[({2-[2-(4-methylphenyl)ethyl]-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid{4-[({2{[(2,4-difluorophenyl)thio]methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid{4-[({2-[(3,5-dimethylphenyl)thio]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid{4-[({2{[(4-tert-butylphenyl)thio]methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid{2-methyl-4-[({3-{[methyl(phenyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid{2-methyl-4-[({2-(2-pyridin-4-ylethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid hydrochloride{4-[({2-isobutyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid{2-methyl-4-[({2{[methyl(pyridin-3-yl}methyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid hydrochloride{4-[({2{[cyclohexyl(methyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid hydrochloride{2-methyl-4-[({2{[methyl(2-phenylethyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid hydrochloride[2-methyl-4-(1-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethoxy)phenoxy]aceticacid[4-({3-[(isopropylthio)methyl]-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)-2-methylphenoxy]aceticacid[2-methyl-4-(1-{5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethoxy)phenoxy]aceticacid[2-methyl-4-(1-{5-[4-(trifluoromethyl)phenyl]thien-3-yl}ethoxy)phenoxy]aceticacid[2-methyl-4-(phenyl{5-[4-(trifluoromethyl)phenyl]thien-3-yl}methoxy)phenoxy]aceticacid2-methyl-2-[2-methyl-4-(phenyl{5-[4-(trifluoromethyl)phenyl]thien-3-yl}methoxy)phenoxy]propanoicacid{2-methyl-4-[({3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid[4-({5-[2,5-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)-2-methylphenoxy]aceticacid[4-({5-[2,3-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)-2-methylphenoxy]aceticacid[2-methyl-4-({3-methyl-5-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]thien-2-yl}methoxy)phenoxy]aceticacid[4-({5-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)-2-methylphenoxy]aceticacid
 18. A compound according to claim 1 selected from:{2-methyl-4-[({3-methyl-5-[4-(trifluoromethyl)phenyl]-2-furyl}methyl)thio]phenoxy}aceticacid{2-methyl-4-[({3-methyl-4-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid[4-({[5-(4-chlorophenyl)-2-methyl-3-furyl]methyl}thio)-2-methylphenoxy]aceticacid{2-methyl-4-[({2-(trifluoromethyl)-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid[2-methyl-4-(2-{4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}ethyl)phenoxy]aceticacid[2-methyl-4-(2-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethyl)phenoxy]aceticacid(4-{2-[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]ethyl}-2-methylphenoxy)aceticacid3-[4-({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)phenyl]propanoicacid{2-methyl-4-[({3-(phenoxymethyl)-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid3-[2-methyl-4-({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)phenyl]propanoicacid{4-[({2-[(benzylthio)methyl]-5[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid{4-[({2-[(isopropylthio)methyl]-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid{2-methyl-4-[({2{[methyl(phenyl)amino]methyl}-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid[2-methyl-4-(2-{2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}ethyl)phenoxy]aceticacid3-[2-methyl-4-(2-{3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}ethyl)phenyl]propanoicacid[2-methyl-4-({2-methyl-5-[4-(trifluoromethyl)phenyl]thien-3-yl}methoxy)phenoxy]aceticacid{4-[({2-isopentyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid{2-methyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]thien-3-yl}methyl)thio]phenoxy}aceticacid[4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-(trifluoromethyl)phenoxy]aceticacid
 19. A compound according to claim 1 selected from:{4-[({3-ethyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]-2-methylphenoxy}aceticacid[4-({[5-(4-chlorophenyl)-2-(trifluoromethyl)-3-furyl]methyl}thio)-2-methylphenoxy]aceticacid[2-methyl-4-({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methoxy)phenoxy]aceticacid{2-methyl-4-[({3-methyl-5-[4-(trifluoromethyl)phenyl]thien-2-yl}methyl)thio]phenoxy}aceticacid{2-methyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid{2-ethyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid{2-isopropyl-4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}aceticacid[2-methyl-4-({3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methoxy)phenoxy]aceticacid{4-[({2-[(benzylthio)methyl]—[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]-2-methylphenoxy}aceticacid
 20. A pharmaceutical composition comprising a compound of any ofclaims 1-19.
 21. A pharmaceutical composition according to claim 3further comprising a pharmaceutically acceptable diluent or carrier. 22.A compound according to any of claims 1-21 for use In therapy.
 23. Useof a compound according to any of claims 1-19 for the manufacture of amedicament for the prevention or treatment of a hPPAR mediated diseaseor condition.
 24. Use according to claim 23 wherein the hPPAR mediateddisease or condition is dyslipidemia, syndrome X, heart failure,hypercholesteremia, cardiovascular disease, type II diabetes mellitus,type 1 diabetes, insulin resistance hyperlipidemia, obesity, anorexiabulimia, inflammation and anorexia nervosa.
 25. A method of treatment ofa hPPAR mediated disease or condition comprising administering atherapeutically effective amount of a compound according to any ofclaims 1-19.
 26. A method according to claim 24 wherein the hPPARmediated disease or condition is dyslipidemia, syndrome X, heartfailure, hypercholesteremia, cardiovascular disease, type II diabetesmellitus, type 1 diabetes, insulin resistance hyperlipidemia, obesity,anorexia bulimia, inflammation and anorexia nervosa.